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Consensus in Pediatrics

Epilepsy Diagnosis and Treatment In Infants and Children


Series Editors: Jeffrey S. Hyams, MD Leonard G. Feld, MD, PhD, MMM
Guest Editors: Gregory L. Holmes, MD Phillip L. Pearl, MD Deepak K. Lachhwani, MB.BS, MD

VOL. 1, NO. 10

Series Editors
Jeffrey S. Hyams, MD Professor of Pediatrics University of Connecticut School of Medicine Farmington, Connecticut Head, Division of Digestive Diseases and Nutrition Connecticut Childrens Medical Center Hartford, Connecticut
Correspondence: Jeffrey S. Hyams, MD Division of Digestive Diseases and Nutrition Connecticut Childrens Medical Center 282 Washington Street Hartford, CT 06106 Tel: (860) 545-9532 Fax: (860) 545-9561 E-mail: jhyams@ccmckids.org

Leonard G. Feld, MD, PhD, MMM Sara H. Bissell & Howard C. Bissell Endowed Chair in Pediatrics and Chief Medical Officer Levine Childrens Hospital at Carolinas Medical Center Clinical Professor of Pediatrics The University of North Carolina School of Medicine
Correspondence: Leonard G. Feld, MD, PhD, MMM Department of Pediatrics Levine Childrens Hospital P.O. Box 32861 Charlotte, NC 28232 Tel: (704) 381-6802 Fax: (704) 381-6841 E-mail: leonard.feld@carolinashealthcare.org

Medical and drug information is constantly evolving because of ongoing research and clinical experience that are often subject to interpretation. While care has been taken to ensure the accuracy of the information presented, the reader is advised that Mead Johnson & Company, and the authors, editors, reviewers, contributors, and publishers of this material are not responsible for the continued currency of the information contained in this material, or any errors or omissions that might appear in this material, or for any consequences arising out of, or resulting from, the use of the material for any purpose or reason whatsoever. Because of the dynamic nature of medical and drug information, readers are advised that decisions regarding drug or any other therapy must be based on the independent judgment of the clinician, information about a drug (eg, as reflected in the literature), and changing medical practices. The Editors and Mead Johnson & Company

Preface
The scope and complexity of pediatric practice continues to expand. With the proliferation of medical information, pediatric expertise for common and sporadic disorders is sought from a variety of medical and surgical specialists. In some instances, opinions by two or more specialists differ in the approach to the diagnosis and management of a common problem. As the medical profession continues to seek answers or consensus for common as well as complex conditions, we have attempted to make the process easier. Consensus in Pediatrics presents a unique series of monographs on selected disease entities from a group of pediatric specialists. Our hope is to bring a balanced review from leaders in the fields of pediatric medicine and surgery. This series is truly an opportunity to share a special compendium of information in a format different from traditional publications. The first monograph, Recurrent Abdominal Pain, was distributed to pediatric healthcare providers in the fall of 2001. In subsequent issues, we have discussed childhood asthma, urinary tract infections, obesity, growth, psychopharmacology, fever, colic, and immunizations. The tenth monograph addresses the important topic of epilepsy. As noted by our specialists, pediatric epilepsy is a disorder with a significant impact on a large number of children. Our panel of experts, Drs. Gregory Holmes, Phillip Pearl, and Deepak Lachhwani, present an understandable classification of epilepsy, discuss the increasing number of choices for antiepileptic drugs, and finally review the potential role of surgery for children with refractory seizures. Their presentations make these often difficult topics much clearer, and our hope is that readers will be better equipped to communicate with neurology colleagues as well as placing different therapies into perspective for patients and families. The Editors, in consultation with our general pediatric community, determine the selection of our topics, contributors, and content. We hope you consider Consensus in Pediatrics a valuable and rich educational resource for your practice. Please feel free to share this information with your colleagues, residents, and students. We also ask for your comments on each monograph and ideas for future topics. We hope this issue will give you guidance in the care of challenging cases in pediatrics. We are grateful to Mead Johnson Nutritionals for the funding of this publication.

Sincerely,

Jeffrey S. Hyams, MD jhyams@ccmckids.org Leonard G. Feld, MD, PhD, MMM leonard.feld@carolinashealthcare.org

The opinions and statements contained in this monograph have not been approved by Mead Johnson & Company, and Mead Johnson & Company will not be held responsible for any statements or opinions contained in this monograph.

Table of Contents
Partial and Generalized Seizures
Introduction ................................................................................................................................................................1 Diagnosis ....................................................................................................................................................................1 Diagnostic Tests .........................................................................................................................................................1 Neuroimaging.............................................................................................................................................................1 Other Testing ..............................................................................................................................................................2 Classification of Seizures and Epilepsy.....................................................................................................................2 Simple partial seizures ........................................................................................................................................3 Complex partial seizures.....................................................................................................................................3 Etiology of partial seizures .................................................................................................................................3 Generalized Seizures ..................................................................................................................................................3 Generalized tonic-clonic seizures .......................................................................................................................3 Absence seizures.................................................................................................................................................4 Clonic seizures ....................................................................................................................................................4 Myoclonic seizures .............................................................................................................................................4 Tonic seizures......................................................................................................................................................5 Atonic seizures....................................................................................................................................................5 Etiology of generalized seizures.........................................................................................................................5 Epileptic Syndromes ..................................................................................................................................................5 Idiopathic-related Partial Epilepsies ..........................................................................................................................5 BECTS ................................................................................................................................................................6 CEOP...................................................................................................................................................................7 Generalized Syndromes .............................................................................................................................................7 Absence seizures.................................................................................................................................................7 Childhood absence epilepsy (pyknolepsy) .........................................................................................................7 Juvenile absence epilepsy ...................................................................................................................................7 Juvenile Myoclonic Epilepsy (JME) ..................................................................................................................7 Infantile spasms ..................................................................................................................................................8 Epilepsy with myoclonic-astatic seizures...........................................................................................................8 Lennox-Gastaut syndrome..................................................................................................................................8 Severe myoclonic epilepsy in infancy................................................................................................................9 Summary.....................................................................................................................................................................9 References ................................................................................................................................................................10

Antiepileptic Drug Therapy in Children


Introduction: Scope of the Problem .........................................................................................................................11

The Antiepileptic Drugs ...........................................................................................................................................12 Overview...........................................................................................................................................................12 The Traditional Drugs ..............................................................................................................................................13 Phenobarbital ....................................................................................................................................................13 Phenytoin ..........................................................................................................................................................13 Carbamazepine..................................................................................................................................................14 Valproic Acid/Valproate....................................................................................................................................14 Ethosuximide ....................................................................................................................................................15 The New AEDs ........................................................................................................................................................15 Felbamate ..........................................................................................................................................................15 Gabapentin ........................................................................................................................................................15 Lamotrigine.......................................................................................................................................................16 Topiramate.........................................................................................................................................................16 Tiagabine...........................................................................................................................................................16 Levetiracetam....................................................................................................................................................16 Oxcarbazepine...................................................................................................................................................17 Zonisamide........................................................................................................................................................17 Pregabalin..........................................................................................................................................................17 Success and Failures: Discontinuation vs Futility of Therapy................................................................................17 Summary ..................................................................................................................................................................18 References ................................................................................................................................................................18

Epilepsy Surgery in the Treatment of Medically Refractory Focal Epilepsy


Introduction ..............................................................................................................................................................21 Medically Refractory Focal Epilepsy ......................................................................................................................21 Identification of Epilepsy Surgery Candidates ........................................................................................................21 Temporal Lobe Epilepsy ..........................................................................................................................................22 Illustrative Case 1 .............................................................................................................................................23 Extratemporal and Multilobar of Hemispheric Epilepsy ........................................................................................24 Illustrative Case 2 .............................................................................................................................................24 Illustrative Case 3 .............................................................................................................................................26 Risks of Ongoing Seizures.......................................................................................................................................28 Timing of Surgery ....................................................................................................................................................28 Summary ..................................................................................................................................................................29 References ................................................................................................................................................................29

Partial and Generalized Seizures


Gregory L. Holmes, MD Pediatric Neurologist Dartmouth-Hitchcock Medical Center Professor of Medicine (Neurology) and Pediatrics Dartmouth Medical School

Introduction
A seizure is a paroxysmal disorder characterized by an abnormal excessive, hypersynchronous discharge of neurons which results in an alteration of function of the patient. This alteration of function can be quite dramatic, such as during a generalized tonicclonic (grand mal) seizure, or much more subtle, such as during an absence (petit mal) seizure. Epilepsy is a condition characterized by repeated, unprovoked seizures. If the seizures are consistently provoked, such as by fever or hypoglycemia, the term epilepsy should not be used. Epilepsy is not a single disorder, but, rather, a symptom of underlying brain dysfunction. Although epilepsy is often a chronic disorder, many children will go into remission.1 Epilepsy is common, sparing no age, race, or ethnic background. The incidence of epilepsy is approximately 1%,2 making it a common neurological condition. Epilepsy is most common in the first year of life and approximately 75% of epilepsy begins during childhood.

There are many paroxysmal disorders that resemble seizures. Episodes such as breath-holding, syncope, migraine, tics, night terrors, and sleepwalking may resemble seizures. The timing of the event is important. Nocturnal epileptic seizures typically occur in the early morning hours, while sleep disorders such as night terrors typically occur several hours after the child falls asleep. If the event always occurs after the child has been crying, the child likely has breathholding attacks. If there is doubt about the diagnosis, it is usually better to wait before beginning therapy.

Diagnostic Tests
The EEG is one of the most valuable tests used in the evaluation of children with possible epileptic seizures. However, the EEG is rarely diagnostic of epilepsy, unless the patient fortuitously has a seizure while having the test. The one exception is in absence epilepsy, where seizures are frequently elicited by hyperventilation during the EEG. Nevertheless, spikes, sharp waves, and spike-wave discharges on the EEG can strongly support a diagnosis of epilepsy. The EEG should always be used within the context of the history. EEGs can be abnormal in children without seizures. Conversely, normal EEGs can be seen in patients with epilepsy. A routine EEG should be obtained for any child with a history compatible with epileptic seizures. The EEG should be recorded during both the awake and sleep states, as well as during hyperventilation and photic stimulation. If the EEG is abnormal, and there is a high suspicion for epileptic seizures, repeating the study may increase the yield. The yield of the EEG can also be increased by obtaining a 24-hour ambulatory EEG.

Diagnosis
The history and neurological examination are the cornerstones of neurological diagnosis. Historical features to note, when dealing with a child with a possible seizure, include the description of the event, precipitants, and duration. A family history of epilepsy should always be ascertained. Of particular importance in the history is the description of the initial signs or symptoms. For example, the approach for a child with an aura prior to a generalized tonicclonic seizure is quite different from that used for a child who has a generalized tonic-clonic seizure without an aura. In the former case, it is likely the child has a partial onset to the seizure, increasing the chances that a structural lesion is responsible for the seizure, while in the latter instance, it is likely the child has a genetic condition. Postictal features can also be helpful. In absence seizures, there is a rapid offset and the child quickly returns to baseline activity, whereas in complex partial seizures, some confusion and tiredness is common following the event.
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Neuroimaging
The MRI is the preferred form of neuroimaging for children with seizures. The majority of patients undergoing an epilepsy evaluation should have an MRI scan. Exceptions include children with typical absence seizures, juvenile myoclonic epilepsy, and benign Rolandic epilepsy. The diagnostic yield of the MRI is highest in children with complex partial seizures, symptomatic epilepsy, and abnormal neurological examinations. While CT scans are often used in the acute setting, to rule out a neoplasm, hemorrhage, or tumor, the MRI is far more sensitive and is the neuroimaging test of choice.

Other Testing
The clinical situation and the type of seizure and syndrome dictate the type of workup. A child presenting with a first seizure should have electrolytes and a serum glucose taken. In a child whose first seizure occurs in the context of a febrile illness, a spinal tap, to rule out infection, and CBC are usually indicated. Children with infantile spasms and other refractory epilepsies should have a metabolic workup, which typically includes serum amino acids, urine organic acids, serum biotinidase, lactate, and pyruvate. Children whose epilepsy occurs in the context of developmental regression need a workup for a degenerative disease. Children with a family history of seizures, or specific phenotypic features, may benefit from genetic testing. For example, children with tuberous sclerosis, Angelman syndrome, or Rett syndrome often present with seizures. Common causes of seizures in different age groups are listed in Table 1.
Table 1: Common Causes of Seizures as a Function of Age

Classification of Seizures and Epilepsy


Once seizures are suspected, the clinician should attempt to classify the seizure. Classification of the seizure will help determine the type and extent of the evaluation and also aid in the selection of the appropriate antiepileptic drug. The International Classification of Epileptic Seizures is presented in Table 2.
Table 2: Classification of Epileptic Seizures3

Neonatal (Birth1 Month) Hypoxia-ischemia Intracranial hemmorrhage Intracerebral Intraventricular Subdural Subarachnoid Hypocalcemia Hypomagnesemia Hypoglycemia Hyponatremia/hypernatremia Infection Congenital (intrauterine eg, toxoplasmosis, rubella) Postnatal CNS malformation Inborn errors of metabolism Drug withdrawal Infancy (1 Month2 Years) Infection Meningitis Encephalitis Trauma Neoplasms Degenerative disorders Genetic disorders Childhood and Adolescence Infection Meningitis Encephalitis Trauma Neoplasms Degenerative disorders Genetic disorders 2

Partial seizures Simple partial seizures (consciousness not impaired) With motor symptoms Focal motor without spread Focal motor with spread (Jacksonian march) Versive Postural Phonatory (vocalization or arrest of speech) With somatosensory or special-sensory symptoms (simple hallucinationstingling, light flashes, buzzing) Somatosensory Visual Auditory Olfactory Gustatory Vertiginous With autonomic symptoms or signs (including epigastric sensation, pallor, sweating, flushing, piloerection, and pupillary dilation) With psychic symptoms (disturbance of higher cerebral function) Dysphasic Dysmnesic Cognitive Affective Illusions Structured hallucination Complex partial seizures (with impairment of consciousness) Simple partial onset followed by impairment of consciousness With impairment of consciousness at onset Partial seizures evolving to secondarily generalized seizures Simple partial seizures evolving to generalized seizures Complex partial seizures evolving to generalized seizures Simple partial seizures evolving to complex partial seizures evolving to generalized seizures Generalized seizures Absence seizures Typical absence Impairment of consciousness only With mild clonic components With atonic components With tonic components With automatisms With autonomic components Atypical absence Myoclonic seizures Clonic seizures Tonic seizures Tonic-clonic seizures Atonic seizures (astatic)
Adapted from Commission on Classification and Terminology of the International League Against Epilepsy.3

Seizures are classified into 2 broad categories: (a) partial seizures (seizures beginning in a limited location in the brain) and (b) generalized seizures (seizures that are bilaterally symmetrical and without focal onset). Seizures are then further classified depending on the exact clinical and EEG manifestations of the seizure. Simple partial seizures. The signs or symptoms of simple partial seizures depend on the location of the focus of the seizure. Seizures involving the motor cortex most commonly consist of rhythmic to semirhythmic clonic activity of the face, arm, or leg. There is usually no difficulty in diagnosing this type of seizure. Seizures with somatosensory, autonomic, and psychic symptoms (hallucinations, illusions, dj vu) may be more difficult to diagnose. Psychic symptoms usually occur as a component of a complex partial seizure. Simple partial seizures can occur at any age and can evolve into complex partial seizures or secondarily generalized tonic-clonic seizures. Complex partial seizures. Complex partial seizures (CPS), formerly termed temporal lobe or psychomotor seizures, are one of the most common seizure types encountered in both children and adults. CPS may be preceded by a simple partial seizure, which may serve as a warning to the patient (ie, aura) that a more severe seizure in pending. It is important to recognize that the aura may enable the clinician to determine the cortical area from which the seizure is beginning. By definition, all patients with CPS have impairment of consciousness. The impairment of consciousness may be subtle. For example, the patient may either not respond to commands or respond in an abnormally slow or inaccurate manner. While CPS may be characterized by simple staring and impaired responsiveness, behavior is usually more complex during the seizure. Automatisms, semi-purposeful behaviors of which the patient is unaware and subsequently cannot recall, are common during the period of impaired consciousness. Types of automatisms are quite variable and may consist of activities such as chewing, grimacing, gestures, lip smacking, snapping fingers, and repeating phrases. The patient usually does not recall doing this activity following the seizure. CPS usually last from 30 seconds to several minutes.4 This duration is in contrast to absence seizures, described later, which usually last less than 15 seconds. Most patients have some degree of postictal impairment, such as tiredness or confusion, following a CPS. Like simple partial seizures, complex partial seizures can evolve into secondarily generalized tonic-clonic seizures.
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EEG. The EEG in partial seizures is characterized by focal spikes, sharp waves, or less commonly, focal slowing. There is often a relationship between the location of the spikes and the seizure type (ie, occipital lobe spikes are associated with occipital lobe seizures, while frontal lobe spikes are associated with frontal lobe seizures). However, patients with well documented seizures may have normal interictal EEGs. Figure 1 is an example of right frontal lobe spikes in a child with frontal lobe epilepsy. This childs seizures consisted of left sided clonic movements.
Figure 1: Right Frontal Spikes (arrows) in a 14-Year-Old Child with Frontal Lobe Epilepsy

Etiology of partial seizures. Most patients with partial seizures have postnatally acquired or congenital causes for their epilepsy. Congenital causes include cerebral malformations or intrauterine strokes. Postnatal causes include trauma, tumors, mesial temporal sclerosis as a result of prolonged febrile seizures, infection, or cerebrovascular disorders.

Generalized Seizures
Generalized tonic-clonic seizures. Generalized tonic-clonic (GTC) seizures are characterized by loss of consciousness, which occurs simultaneously with the onset of a generalized stiffening of flexor or extensor muscles (termed tonic phase). The old term for this type of seizure was grand mal. Following the tonic phase, generalized jerking of the muscles (clonic activity) occurs. The eyes are open during a GTC. The seizures are dramatic and there is rarely any difficulty making the correct diagnosis. Seizures that begin suddenly, with bilateral tonic posturing without a focal onset, are classified as primary GTC. Some patients may have a simple partial seizure (aura) preceding the loss of consciousness and generalized tonic-clonic activity. As described above, this

indicates the seizure was simple partial in onset. Patients may have a complex partial seizure with secondary generalization. GTCs are always associated with deep postictal sleep. EEG. The interictal EEG in patients with GTCs that have a partial onset have similar features to what is described above for patients with partial seizures. Patients with primary generalized GTC may have a variety of findingsvarying from a normal EEG, generalized spike-wave discharges, or multifocal spikes, usually involving the frontal lobes. Absence seizures. Absence seizures are generalized seizures, indicating bihemispheric initial involvement clinically and electroencephalographically.5 Absence seizures have an abrupt onset and offset. There is typically a sudden cessation of activities, with a blank, distant look to the face. As the seizure continues, there are often automatisms and mild clonic motor activity, such as jerks of the arms and eye blinking. Typical absence seizures consist of the sudden onset of impaired consciousness, usually associated with a blank or distant facial appearance. Children usually have other behavioral changes during the seizures, including automatisms and eye blinking. In an untreated child, typical absence seizures are almost always precipitated by hyperventilation. Atypical absence seizures are characterized as having more pronounced changes in tone and longer duration than typical absence seizures. However, there is a considerable overlap between typical and atypical absence seizures.6 Both start abruptly, without an aura, last from a few seconds to half a minute, and end abruptly. EEG. The EEG signature of a typical absence seizure is the sudden onset of 3-Hz generalized symmetrical spike- or multiple spike-wave complexes (Figure 2).
Figure 2: Typical Absence Seizure in an 8-Year-Old Child with Absence Epilepsy
Note regular 3 cycle/second spike and wave discharges.

The voltage of the discharge is often maximal in the frontal-central regions. The ictal discharges during an atypical absence seizure are more variable. They typically occur at frequencies between 1.52.5 Hz and are irregular or asymmetrical in voltage (Figure 3).
Figure 3: Atypical Absence Seizure in 9-Year-Old Child with Lennox-Gastaut Syndrome
Note the irregular spike and wave activity.

Clonic seizures. Clonic seizures are similar to GTC seizures, but only have rhythmic or semi-rhythmic contractions of a group of muscles. These jerks can involve any muscle group, although the arms, neck, and facial muscles are most commonly involved. Clonic seizures are much more common in children than adults. EEG. The interictal EEG pattern seen in patients with clonic seizures is similar to those with GTCs. The ictal pattern usually consists of spike-wave discharges. Myoclonic seizures. Myoclonic seizures are characterized by sudden, brief (<350 msec), shock-like contractions that may be generalized or confined to the face and trunk, one or more extremities, or even to individual muscles or groups of muscles. Myoclonic seizures result in short bursts of synchronized electromyographic activity. The contractions of muscles are quicker than the contractions with clonic seizures. Any group of muscles can be involved in the jerk. Myoclonic seizures may be dramatic, causing the patient to fall to the ground, or be quite subtle, resembling tremors. Because of the brevity of the seizures, it is not possible to determine if consciousness is impaired. Myoclonus may occur as a component of an absence seizure or at the beginning of a GTC seizure. EEG. The interictal EEG pattern seen in patients with myoclonic seizures typically consists of generalized spike-wave discharges.
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Tonic seizures. Tonic seizures are brief seizures (usually less than 60 seconds) consisting of sudden onset of increased tone in the extensor muscles. If standing, the child usually falls to the ground. The seizures are longer than myoclonic seizures. Electromyographic activity is dramatically increased in tonic seizures. There is impairment of consciousness during the seizure, although in short seizures this may be difficult to assess. EEG. The EEG ictal manifestations of tonic seizures usually consist of bilateral synchronous spikes of 1025 Hz of medium to high voltage with a frontal accentuation.7 Marked suppressiontermed desynchronizationmay also occur (Figure 4).
Figure 4: Desynchronization of EEG (arrow) During Tonic Seizure in an 11-Year-Old Child with Tonic Seizures

identified for these conditions. Atypical absences, tonic, and myoclonic seizures are usually associated with acquired disorders. Atypical absence, tonic, and atonic seizures are often seen in the context of Lennox-Gastaut syndrome, which is discussed on page 8.

Epileptic Syndromes
Once the seizure type has been identified, it is very helpful for the clinician to try to determine the epileptic syndrome. An epileptic syndrome is a cluster of clinical and electroencephalographic features that occur together more commonly than by chance. Epileptic syndrome identification aids in identifying etiology and provides the clinician with guidance regarding long-term prognosis. An example of an epileptic syndrome would be juvenile myoclonic seizures (JME). The seizure types are generalized tonic-clonic, absence, or myoclonic and often occur upon awakening. The seizures begin in adolescence or early adulthood in an otherwise healthy individual. The interictal EEGs show spike-and-wave activity at a frequency of 3.56.0 Hz, while neuroimaging is normal. Although the seizures are usually controlled with antiepileptic drugs, the condition is lifelong. A single gene mutation has not been identified, and many investigators feel the condition likely involves multiple genes. Once diagnosed with JME, the patient can be provided specific information regarding prognosis and treatment. The International Classification of the Epilepsies and Epileptic Seizures (Table 3 on page 6) divides seizure syndromes into 2 major categories.8 The first category distinguishes generalized seizures (generalized epilepsies) from epilepsies with partial or focal seizures (localization-related partial or focal epilepsies). The other category separates epilepsies of known etiology (symptomatic or secondary epilepsies) from those that are idiopathic (primary) or cryptogenic. Space limitations prohibit an indepth discussion of all syndromes. Therefore, only the more common syndromes will be discussed.

Atonic seizures. Atonic (astatic) seizures, or drop attacks, are characterized by a sudden loss of muscle tone. They begin suddenly and without warning, causing the patient, if standing, to fall quickly to the floor. Since there may be a total lack of tone, the child has no means to protect himself, and injuries may occur. The attack may be fragmented and lead to dropping of the head, with slackening of the jaw or dropping of a limb. In atonic seizures, there is a loss of electromyographic activity. EEG. The interictal EEG has features similar to those seen in the other generalized seizures. Atonic seizures are usually associated with rhythmic spikeand-wave complexes, varying from slow, 12 Hz, to more rapid, irregular spike or multiple spike-andwave activity. Many children with atonic seizures have background slowing as well. Etiology of generalized seizures. It is likely that most children with generalized seizures have a genetic basis for the disorder. This is particularly the case for primary generalized tonic-clonic and typical absence seizures, although single genes have not been
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Idiopathic-related Partial Epilepsies


The diagnostic criteria for idiopathic-related partial epilepsies include: (a) normal neurological examinations; (b) normal intelligence; (c) normal neuroimaging; (d) a family history of seizures, especially benign types; (e) brief seizures that are stereotyped in clinical manifestation; (f) frequent nocturnal occurrence of the seizures; (g) seizures that are easily controlled with antiepileptic drugs; and (h) frequent

Table 3:

International Classification of Epilepsies and Epileptic Syndromes10


3. Epilepsy with myoclonic-astatic seizures 4. Epilepsy with mycolonic absences C. Symptomatic 1. Nonspecific etiology a. Early myoclonic encephalopathy b. Early infantile epileptic encephalopathy with suppression bursts c. Other symptomatic generalized epilepsies not defined above 2. Specific syndromes a. Epileptic seizures may complicate many disease states III. Epilepsies and syndromes undetermined as to whether they are focal or generalized A. With both generalized and focal seizures 1. Neonatal seizures 2. Severe myoclonic epilepsy in infancy 3. Epilepsy with continuous spike waves during slow-wave sleep 4. Acquired epileptic aphasia (Landau-Kleffner syndrome) 5. Other undetermined epilepsies not defined above B. Without unequivocal generalized or focal features IV. Special syndromes A. Situation-related seizures 1. Febrile convulsions 2. Isolated seizures or isolated status epilepticus 3. Seizures occurring only when there is an acute metabolic or toxic event, due to factors such as alcohol, drugs, eclampsia, or nonketotic hyperglycemia

I. Localization-related (focal, local, partial) epilepsies and syndromes A. Idiopathic with age-related onset 1. Benign childhood epilepsy with central-temporal spikes (benign rolandic epilepsy) 2. Childhood epilepsy with occipital paroxysms (benign occipital epilepsy) 3. Primary reading epilepsy B. Symptomatic 1. Chronic progressive epilepsia partialis continua of childhood (Kojewnikow syndrome) 2. Syndromes characterized by seizures with specific modes of precipitation C. Cryptogenic II. Generalized epilepsies and syndromes A. Idiopathic (with age-related onset; listed in order of age) 1. Benign neonatal familial convulsions 2. Benign neonatal convulsions 3. Benign myoclonic epilepsy in infancy 4. Childhood absence epilepsy (pyknolepsy) 5. Juvenile absence epilepsy 6. Juvenile myoclonic epilepsy (impulsive petit mal) 7. Epilepsy with grand mal seizures on awakening 8. Other generalized idiopathic epilepsies not defined above 9. Epilepsies with seizures precipitated by specific modes of activation B. Cryptogenic or symptomatic (in order of appearance) 1. West syndrome (infantile spasms) 2. Lennox-Gastaut syndrome
Adapted from Talwar.10

remission of the seizures during adolescence.9 The principal electroencephalographic features include: (a) normal background activity; (b) spikes with a characteristic morphology and location; (c) activation during sleep; and (d) occasional generalized spike-wave discharges.11 Two idiopathic localization-related epileptic syndromes have been delineated: benign childhood epilepsy with centro-temporal spikes (BECTS) and childhood epilepsy with occipital paroxysms (CEOP).8 BECTS. BECTS is a genetic disorder confined to children, characterized by nocturnal generalized seizures of probable focal onset, diurnal simple partial seizures arising from the lower Rolandic area, and an EEG pattern consisting of a midtemporal-central spike foci.12-14 The syndrome is also termed benign Rolandic epilepsy because of its characteristic featurepartial seizures involving the region around the lower portion of the central gyrus of Rolando. The characteristic features of daytime seizures include (a) somatosensory stimulation of the oral-buccal cavity; (b) speech arrest; (c) preservation of consciousness; (d) drooling; and (e) tonic or tonic-clonic activity of the face. Less often, the somatosensory
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sensation spreads to the face or arm. Most attacks involve the face and arrest of speech may initiate the attack or occur during its course. Consciousness is rarely impaired during the daytime attacks, although, because of the motor involvement, the child cannot speak. Often, the childs gestures will indicate to the parents that the child is totally aware during the event. The disorder always begins during childhood. The age range is from 313 years, with a peak of age incidence between 78 years of age. The disorder occurs somewhat more frequently in boys than girls. Most children have normal neurological examinations and intelligence. While antiepileptic drug therapy is often not necessary, when it is administered, most children will respond to the therapy. Virtually all children stop having seizures by age 16. EEG. The characteristic interictal EEG abnormality is a high-amplitude, usually diphasic, spike with a prominent following slow wave. The spikes or sharp waves appear singly or in groups in the midtemporal and central (Rolandic) region (C3, C4) (Figure 5).

Figure 5: Rolandic Spikes (arrows) in 12-Year-Old Child with Epilepsy with CentroTemporal Spikes (BECTS)

and juvenile absence seizure syndromes. Atypical absence seizures most commonly occur in LennoxGastaut syndrome. There are 4 syndromes in which absence seizures are a major component: childhood absence epilepsy (pyknolepsy), juvenile absence epilepsy, juvenile myoclonic epilepsy (impulsive petit mal), and epilepsy with myoclonic absences. The absence epilepsies appear to have a complex genetic basis and some may be autosomal dominant with an age-dependent, high penetrance. Childhood absence epilepsy (pyknolepsy). Pyknolepsy describes typical absence seizures (ie, both simple and complex) in children between ages 35 years and puberty, who are otherwise normal. There is a strong genetic predisposition, and girls are more frequently affected. The absences are very frequent, occurring multiple times daily, and tend to cluster. The absences typically remit during adolescence, but generalized tonic-clonic seizures may develop. EEG. The EEG reveals a bilateral, synchronous symmetrical 3-Hz spike-and-wave discharge, with normal interictal background activity (Figure 2 on page 4). Juvenile absence epilepsy. Juvenile absence epilepsy begins around puberty and differs from pyknolepsy in that the seizures are less frequent. Generalized tonicclonic seizures are common in the disorder. This syndrome blurs with juvenile myoclonic epilepsy, as generalized tonic-clonic seizures and myoclonic seizures are often seen on awakening. The incidence in boys and girls is similar. EEG. The EEG findings are similar to childhood absence epilepsy except that the spike-waves are often slightly faster than 3 Hz. Juvenile myoclonic epilepsy (JME). JME is a familial disorder that typically begins in the second decade of life and is characterized by mild myoclonic seizures, generalized tonic-clonic, or clonic-tonicclonic seizures (a variation of GTC seizures in which there is an initial clonic phase), and occasionally, absence seizures. The myoclonic seizures are usually mild to moderate in intensity and involve the neck, shoulders, and arms. They can occur either singularly or repetitively and may cause the patient to drop objects. Rarely, the jerks may involve the legs and cause the patient to fall to the ground. There have been multiple attempts at determining the gene(s) responsible for the disorder. It now appears clear there is not a single gene that accounts for all of the cases and that
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CEOP. There are 2 distinct forms of CEOP. The early onset type, or Panayiotopoulos syndrome, occurs in young children, with a peak onset at 5 years of age. The late onset, or Gastaut type, has an age of onset of around 89 years. Both syndromes are associated with occipital spikes. Panayiotopoulos syndrome is characterized by ictal vomiting and deviation of the eyes, often with impairment of consciousness and progression to generalized tonic-clonic seizures.15,16 The seizures are infrequent and often solitary, but in approximately a third of the children, the episodes evolve into partial status epilepticus. Two-thirds of the seizures occur during sleep. The late onset, or Gastaut type, consist of brief seizures with mainly visual symptoms, such as elementary visual hallucinations, illusions, or amaurosis, followed by convulsions. Postictal migraine headaches occur in about half of the patients.10,17 EEG. The interictal EEG in Panayiotopoulos syndrome is characterized by normal background activity, with spikes at a variety of locations. Approximately two-thirds of patients have one EEG with occipital spikes.18 Spikes are similar in morphology and amplitude to those seen in benign Rolandic epilepsy and may be eliminated with eye opening.18,19 The spikes may be activated with drowsiness and sleep. In the Gastaut-type of childhood occipital epilepsy, the EEG is characterized by high amplitude (200300 V) spikes, which occur with eye closure.

Generalized Syndromes
Absence seizures. Absence seizures can be classified into 2 subtypes: typical and atypical.5 Typical absence seizures are the primary seizures in both childhood

there is considerable genetic and locus heterogeneity in the disorder. EEG. The interictal EEG in this disorder is distinctive and easily distinguished from other forms of generalized epilepsies. The characteristic feature of the EEG is the fast (3.56 Hz) spike-and-wave and multiple spike-and-wave complexes (Figure 6). This pattern contrasts with the 3-Hz spike-and-wave complexes seen in classic absence seizures and the slow (1.52.5 Hz) spike-and-wave complexes of Lennox-Gastaut syndrome (Figure 3 on page 4).
Figure 6: Rapid Spike-Wave Discharge in 16-Year-Old Patient with Juvenile Myoclonic Epilepsy
Note the faster frequency of the discharges compared to Figures 3 and 4.

Figure 7: Hypsarrhythmia in an 8-Month-Old with Infantile Spasms


EEG shows a chaotic, high amplitude pattern with multifocal spikes and sharp waves.

Epilepsy with myoclonic-astatic seizures. Epilepsy with myoclonic-astatic seizures is characterized by myoclonic and astatic seizures in combination with absence, generalized tonic-clonic, and tonic seizures, beginning during childhood.22-24 In this syndrome, astatic seizures (defined as the inability to stand) occur suddenly, without warning, and the child collapses onto the floor, as if his legs have been pulled from under him. No apparent loss of consciousness accompanies these seizures. At times, the astatic seizures are so short that only a brief nodding of the head and slight flexion of the knees is seen. With few exceptions, the mental and motor development of the children is normal before the onset of the illness. The prognosis is generally more favorable than Lennox-Gastaut syndrome (see below). EEG. The characteristic features of the interictal EEG is rhythmic theta activity in the parietal region, as well as occipital 4-Hz rhythm, which is blocked by eye opening.25,26 The EEG shows single or bursts of spike-and-wave activity.27 The spike-and-wave discharges are irregular in frequency, polymorphic in configuration, and usually occur at a frequency of 23 Hz. Lennox-Gastaut syndrome. Lennox-Gastaut syndrome (LGS) is a mixed seizure disorder in which tonic seizures are a major component, along with a slow spike-and-wave EEG pattern.28-30 The syndrome always begins in childhood. Almost all children with the syndrome are mentally retarded. The child with LGS typically has a mixture of seizure types, the most frequently occurring of which are tonic, tonicclonic, atypical absences, and head drops, which represent a form of atonic or tonic seizures.
8

Infantile spasms. Infantile spasms is a unique and frequently malignant epileptic syndrome confined to infants, usually below the age of one year. The usual characteristic features of this syndrome are tonic or myoclonic seizures, hypsarrhythmic EEGs, and mental retardation.20 This triad of symptoms is referred to as Wests syndrome. Not all infants with infantile spasms conform strictly to this definition. The disorder is also referred to in the literature as massive spasms, salaam seizures, flexion or flexor spasms, jackknife seizures, and massive myoclonic jerks. EEG. Infantile spasms are usually associated with markedly abnormal EEGs. The most commonly found EEG pattern is hypsarrhythmia (Figure 7).21 This pattern consists of high-amplitude slow waves, mixed with spikes and sharp waves whose amplitude and topography vary in an asynchronous manner between the 2 hemispheres. The background activity is completely disorganized and chaotic.

Tonic seizures are a major component of this syndrome. They are typically activated by sleep and may occur repetitively throughout the night. They are much more frequent during non-REM sleep than during wakefulness and usually do not occur during REM sleep. In LGS, tonic seizures are usually brief, lasting from a few seconds to one minute, with an average duration of about 10 seconds. The seizures may cause falls and injury. Eyelid retraction, staring, mydriasis, and apnea are commonly associated and may be the most prominent features. During tonic seizures, the patient is unconscious, although arousal from light sleep may occur. Since the seizures are often very brief, they often go undetected. While atonic seizures are common in this syndrome, they occur less frequently than tonic and myoclonic seizures. Most such seizures are quite brief, lasting 14 seconds. In the briefest attacks, patients may show only head nodding or sagging at the knees. Patients with LGS typically have very frequent seizures, with some children having hundreds of seizures daily.30,31 EEG. The EEG in LGS shows slow spike-andwave discharge superimposed over an abnormal, slow background. The slow spike-and-wave or sharp- and slow-wave complexes consist of generalized discharges, occurring at a frequency of 1.52.5 Hz (Figure 3 on page 4). Many children with LGS will have desynchronization of the EEG during tonic seizures (Figure 4 on page 5).7 Severe myoclonic epilepsy in infancy. Severe myoclonic epilepsy in infancy, also termed Dravet syndrome, is a disorder which typically begins in the first or second year of life, with repeat episodes of severe febrile status epilepticus.32,33 The child then goes on to develop frequent myoclonic seizures. With onset of the afebrile seizures and EEG abnormalities, developmental progress slows, and many of the children develop ataxia, spasticity, and cognitive impairment. This epilepsy is quite resistant to all forms of treatment. At the time of the first febrile seizure, the EEG is usually normal and without any paroxysmal abnormalities. With onset of the myoclonus, generalized spike-and-wave is seen during the seizures. The generalized discharges increase during drowsiness. Focal and multifocal spikes and sharp waves are also seen. De novo truncating mutations of gene coding for the neuronal voltage-gated sodium channel 1 subunit (SCN1A) on 2p24 have been found in severe myoclonic epilepsy in infancy.34,35
9

EEG. At the time of the first febrile seizure, the EEG is usually normal and without any paroxysmal abnormalities. Between age 12 years, the myoclonic seizures begin. The myoclonus can be massive, involving whole muscles, particularly the axial ones, or be barely discernible.33 The jerks can be isolated or occur in flurries. During EEG monitoring, generalized spike-and-wave or polyspike-and-wave activity is seen during the seizures. When absence seizures occur, they are also associated with generalized spikeand-wave activity, usually at a frequency of 3 Hz. The generalized discharges increase during drowsiness.

Summary
Most physicians will not have the opportunity to observe children having seizures in their office. Therefore, making the diagnosis requires a detailed history. The EEG remains a very useful diagnostic test in the diagnosis of seizures, but should be used only within the context of the clinical history. The EEG can support the diagnosis, but it is rarely diagnostic of epilepsy. Once it has been determined a seizure has occurred, the next step is to classify the seizure type. This method will aid in both the diagnostic workup and therapy. If the child has epilepsy, it is incumbent upon the clinician to try to determine whether the child has an epileptic syndrome. Syndrome identification will aid the clinician in determining the appropriate diagnostic studies and therapy.
Correspondence to: Gregory L. Holmes, MD Section of Neurology Dartmouth Medical School One Medical Center Drive Lebanon, New Hampshire 03756 Tel: (603) 650-7610 Fax: (603) 650-6233 E-mail: Gregory.L.Holmes@Dartmouth.edu

References
1. Berg AT, Shinnar S, Levy SR, et al. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia. 2001;42:1553-1562. 2. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia. 1994;35(suppl 2):S1-S6. 3. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981;22:249-260. 4. Holmes GL. Partial seizures in children. Pediatrics. 1986;77:725-731. 5. Pearl PL, Holmes GL. Absence seizures. In: Pellock JM, Dodson WE, Bourgeois BFD, eds. Pediatric Epilepsy. Diagnosis and Treatment. New York: Demos; 2001:219. 6. Holmes GL, McKeever M, Adamson M. Absence seizures in children: clinical and electroencephalographic features. Ann Neurol. 1987;21:268-273. 7. Yaqub HA. Electroclinical seizures in Lennox-Gastaut syndrome. Epilepsia. 1993;34:120-127. 8. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-399. 9. Lerman P, Kivity S. The benign partial nonrolandic epilepsies. J Clin Neurophysiol. 1991;8:275-287. 10. Talwar D, Rask CA, Torres F. Clinical manifestations in children with occipital spike-wave paroxysms. Epilepsia. 1992;33:667-674. 11. Holmes GL. Benign focal epilepsies of childhood. Epilepsia. 1993;34(suppl 3):S49-S61. 12. Holmes GL. Rolandic epilepsy: clinical and electroencephalographic features. Epilepsy Res Suppl. 1992;6:29-43. 13. Lerman P, Kivity S. Benign focal epilepsy of childhood. A follow up study of 100 recovered patients. Arch Neurol. 1975;32:261-264. 14. Ma CK, Chan KY. Benign childhood epilepsy with centrotemporal spikes: a study of 50 Chinese children. Brain Dev. 2003;25:390-395. 15. Panayiotopoulos CP. Benign childhood epileptic syndromes with occipital spikes: new classification proposed by the International League Against Epilepsy. J Child Neurol. 2000;15:548-552. 16. Caraballo R, Cersosimo R, Medina C, Fejerman N. Panayiotopoulos-type benign childhood occipital epilepsy: a prospective study. Neurology. 2000;55:1096-1100. 17. Gastaut H. A new type of epilepsy: benign partial epilepsy childhood with occipital spike-waves. Clin Electroencephalogr. 1982;13:13-22. 18. Panayiotopoulos CP. Benign Childhood Focal Seizures and Related Syndromes. A Clinical guide to Epileptic Syndromes and Their Treatment. Oxfordshire: Bladon Medical Publishing; 2002:89. 19. Panayiotopoulos CP. Benign childhood epilepsy with occipital paroxysms: a 15-year prospective study. Ann Neurol. 1989;26:51-56.
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20. Holmes GL, Vigevano F. Infantile spasms. In: Engel J, Jr., Pedley TA, eds. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott-Raven Publishers; 1997:627. 21. Gibbs EL, Fleming MM, Gibbs FA. Diagnosis and prognosis of hypsarrhythmia and infantile spasms. Pediatrics. 1954;13:66-73. 22. Doose H. Myoclonic-astatic epilepsy. In: Degen R, Dreifuss FE, eds. Benign Localized and Generalized Epilepsies of Early Childhood. Amsterdam: Elsevier Science Publishers, BV; 1992:163. 23. Doose H, Gerken H, Leonhardt R, Vlzke E, Vlz C. Centrencephalic myoclonic-astatic petit mal. Clinical and genetic investigations. Neuropaediatrie. 1970;2:59-78. 24. Panayiotopoulos CP. Idiopathic generalised epilepsies. A Clinical Guide to Epileptic Syndromes and Their Treatment. Oxfordshire: Bladon Medical Publishing; 2002:114. 25. Doose H. Myoclonic astatic epilepsy of early childhood. In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey; 1992:103. 26. Doose H, Gundel A. Four to 7 cps rhythms in the childhood EEG. In: Anderson VE, Hauser WA, Penry JK, Sing CF, eds. Genetic Basis of the Epilepsies. New York: Raven Press; 1982:113. 27. Oguni H, Fukuyama Y, Imaizumi Y, Uehara T. VideoEEG analysis of drop seizures in myoclonic astatic epilepsy of early childhood (Doose syndrome). Epilepsia. 1992;33:805-813. 28. Holmes GL. Myoclonic, tonic, and atonic seizures in children. J Epilepsy. 1988;1:173-195. 29. Genton P, Dravet C. Lennox-Gastaut and other childhood epileptic encephalopathies. In: Engel J Jr, Pedley TA, eds. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott-Raven Publishers; 1997:2355. 30. Markand ON. Slow spike-wave activity in EEG and associated clinical features: often called Lennox or Lennox-Gastaut syndrome. Neurology. 1977;27:746-757. 31. Papini M, Pasquinelli A, Armellini M, Orlandi D. Alertness and incidence of seizures in patients with LennoxGastaut syndrome. Epilepsia. 1984;25:161-167. 32. Nabbout R, Dulac O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol. 2003;20:393-397. 33. Dravet C, Bureau M, Guerrini R, Giraud N, Roger J. Severe myoclonic epilepsy in infants. In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbey; 1992:75. 34. Claes L, Ceulemans B, Audenaert D et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum Mutat. 2003;21:615-621. 35. Scheffer IE, Wallace R, Mulley JC, Berkovic SF. Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome). Brain Dev. 2001;23:732-735.

Antiepileptic Drug Therapy in Children


Phillip L. Pearl, MD Pediatric Neurologist Childrens National Medical Center Associate Professor of Pediatrics and Neurology The George Washington University School of Medicine

seizure during sleep. Factors that have been addressed, but not linked to a heightened recurrence risk, are age of onset, the number of seizures in the first 24 hours, and the duration of the first seizure. When a physician is armed with information about these factors, as well as a syndromic diagnosis that fits the epilepsy, one can proceed more confidently in the decision whether to initiate medication. The presence of a second seizure predicts a 70% chance of a third event in both children and adults.4,5 Most clinicians, therefore, will introduce chronic AED therapy after a second, or sometimes third, seizure. This decision is predicated on the patients personal life circumstances. In the case of an adult or adolescent with driving privileges, even one seizure a year can be catastrophic. In the relatively common syndromes of benign partial epilepsy of childhood such as benign Rolandic epilepsysome patients will have seizures only rarely, and the epilepsy is universally outgrown by the end of adolescence, with or without therapy. Therefore, there are patients who are appropriately not initiated on AED therapy, despite having a lifetime history of multiple seizures. The decision remains an individualized one, based on the risk factors mentioned above. There are, however, important reasons to use AEDs beyond the recurrence risk for future events. One consideration is the increasing evidence that seizures may be associated with deleterious effects on learning and behavior. Certainly seizures and learning disabilities are associated in many patients. There is a higher incidence of ADHD in children with epilepsy, irrespective of sex, seizure type, or location of seizure focus.6 There is also a higher incidence of recognizable behavior problems in children who develop epilepsy, even before their first seizure.7 Recent evidence indicates that recurring seizures are predictably associated with behavior problems early in the course of a seizure disorder in children vs their siblings.8 It is unknown whether this complication is related to a common neurodevelopmental disorder accounting for both the seizures and behavior problems, disruptive effects of seizure activity on behavior, or an adverse psychological response to having seizures. There is also evidence that mental retardation is strongly correlated with poor seizure control in the catastrophic epilepsies.9 Additionally, sudden unexpected death in epilepsy patients (SUDEP) has been associated with onset of epilepsy at an early age, duration of epilepsy, and seizure frequency.10 These considerations highlight the importance of judicious but necessary use
11

Introduction: Scope of the Problem


Seizures and epilepsy are common neurological problems in pediatrics. While epilepsies are a heterogeneous group of disorders, the array of medications available to treat them has rapidly proliferated. This has further complicated the practice of pediatrics vis-vis the child with epilepsy. A stepwise approach to proper diagnosis of the type of seizure and epilepsy syndrome is the optimal way to begin gauging the prognosis of the individual patient and selecting the most appropriate plan of management. The common term used for epilepsy medicationsantiepileptic drugshas been called a misnomer for good reason, since there is little evidence to suggest these medications actually modify the underlying course of the epilepsy. While this term properly replaced the former term of anticonvulsants, emphasizing that not all seizures are convulsive, a more realistic term may be anti-seizure medications. In any case, antiepileptic drugs (AEDs) have become part of standard medical parlance in the current age, and we will grudgingly continue this misuse, acknowledging that we remain largely unable to actually modify the underlying mismatch of cerebral excitation and inhibition that leads to epileptogenesis. The decision to initiate AED therapy in a patient is predicated on knowing the natural history of that patients condition, if that is determinable. While epilepsy is a syndrome of repeated seizures requiring 2 or more events for a definitive diagnosisa number of studies over the past 25 years have addressed the recurrence risk following a first unprovoked seizure. This event is defined as a seizure, or flurry of seizures within 24 hours, in a patient over one month of age, with no history of previous unprovoked seizures.1 There is an overall recurrence risk of approximately 25%50%.2,3 Approximately half of the recurrences will occur within 6 months of the initial seizure, and 80% will occur within 2 years. Risk factors associated with higher chances of recurrence are the presence of an underlying neurodevelopmental abnormality that may explain the etiology of the seizure, an EEG abnormality, or the occurrence of a

of AED therapy, even while we await evidence that these complications of epilepsy can be mitigated by seizure control.

The Antiepileptic Drugs


Overview. AEDs are often divided into 2 categories: traditional medicines and new agents, which is heuristically helpful to clinicians, even if not historically important (Table 1). Nine new antiepileptic medications have been approved for use by the United States Food and Drug Administration since the introduction of felbamate in 1993. There have also been new formulations of older drugs. These alternatives have some advantages in terms of spectrum of action, tolerability, and drugdrug interactions, although the plethora of options has placed new demands on practicing physicians. There are also new drugs in the pipeline, some of which are

available in other countries and used either under study or in compassionate-use protocols approved by institutional review boards in the U.S. Examples of the latter include vigabatrin, clobazam, and midazolam. The process of ethically testing drugs as add-on agents in the most accessible population (ie, adults with partial seizures) has led to a repeating pattern of FDA approval of new AEDs for use as adjuvant therapy in adults with partial seizures, with relatively limited approvals for pediatric indications. The NIH has instituted a pediatric rule to correct this imbalance in preapproval clinical trials, so that more medications are tested in the pediatric population. However, the current situation has relegated the primary indication for these new AEDs to add-on therapies in adult partial epilepsy. Still, the new agents are finding increasing use in the pediatric population, including neonates, children, and adolescents. In general, the

Table 1: AEDs in Pediatrics, by Chronological Order of Introduction and How Supplied Antiepileptic Drug Phenobarbital Phenytoin Year Introduced or FDA Approval 1912 1938 Brand Names and How Supplied 15, 30, 60 mg tablets 20 mg/5 mL solution Dilantin 50 mg chewable tablet; 30, 100, 200, 300 mg extended release capsules; 125 mg/5 mL elixir Cerebyx 50 mg/ml parenteral (for intramuscular or intravenous administration Zarontin 250 mg capsules; 250 mg/5 mL solution Tegretol 100 mg chewable tablets, 200 mg tablets, 100 mg/5 mL Tegretol-XR 100, 200, 400 mg tablets Carbatrol 200 mg, 300 mg tablets Depakote 125 mg sprinkle caps; 125, 250, 500 mg tablets Depakote ER 250, 500 mg tablets Depakene 250 mg/5 mL, 250 mg cap Depacon (intravenous) 500 mg/5 mL Felbatol 400, 600 mg tablets; 600 mg/5 mL Neurontin 100, 300, 400, 600, 800 mg capsules; 250 mg/5 mL Lamictal 5, 25 mg chewable tablets; 25, 100, 150, 200 mg tablets Topamax 15, 25 mg sprinkle capsules; 25, 100, 200 mg tablets Gabatril 2, 4, 12, 16 mg tablets Keppra 125, 250, 500, 750 mg tablets; 500 mg/5 mL Trileptal 150, 300, 600 mg tablets; 300 mg/5 mL Zonegran 25, 100 mg capsules Lyrica 25, 50, 75, 100, 200, 300 mg capsules
12

Ethosuximide Carbamazepine

1960 1974

Valproate

1978

Felbamate Gabapentin Lamotrigine Topiramate Tiagabine Levetiracetam Oxcarbazepine Zonisamide Pregabilin

1993 1994 1994 1996 1997 1999 2000 2000 2005

new agents are often characterized as having more favorable side-effect profiles and fewer drug interactions compared with the more traditional agents,11 although this is far from universally true. Severe idiosyncratic complications, such as aplastic anemia in the case of felbamate and Stevens-Johnson syndrome with lamotrigine, are well recognized with the newer agents. Frankly, there is no consistent or compelling evidence to show that the newer drugs have more efficacy or safety compared to each other or to the older drugs.12

The Traditional Drugs


While bromides are credited for being the first antiepileptic medication prescribed by physicians, their toxicity was an impediment to ongoing use. As a result, phenobarbital, introduced in 1912, is the first medication that remains in active use. More than 20 medications were introduced into the U.S. for epilepsy before the newer agents emerged in the mid1990s, and the traditional drugs in common use are phenobarbital, phenytoin, carbamazepine, and valproate. An additional agent of importance is ethosuximide, as it has particular efficacy for absence (petit mal) seizures. Other older medications with some ongoing use for the chronic prevention of seizures include primidone, clonazepam, and clorazepate. Phenobarbital. Phenobarbital is avoided as a firstline drug for the prevention of epilepsy, with the exception of the first year of life. Its dose-related adverse effects of sedation, irritability, cognitive dysfunction, and ataxia have limited its use to a great extent.13 Children may demonstrate hyperactivity. In clinical practice, however, many patients have been on this agent a long time and find it preferable, to avoid changes in drug therapy when there are no perceived problems with seizure control or adverse effects. Phenobarbital is effective for generalized tonic-clonic and partial seizures.14 Phenobarbital is metabolized in the liver by the cytochrome P450 enzyme system,15 and, further, it is an inducer of that system.16 This is true of other AEDs as well, including phenytoin and carbamazepine. Phenobarbital will reduce the plasma concentration of other AEDs the patient may be using, including carbamazepine, lamotrigine, tiagabine, valproic acid, oxcarbazepine, phenytoin, and zonisamide. It will also reduce levels of warfarin, cyclosporine, theophylline, oral contraceptives, digoxin, and cimetidine. In contrast, phenobarbital levels may be increased as an effect of valproic acid.

Phenobarbital is equally effective to phenytoin in the treatment of neonatal seizures,17 although the efficacy of either agent is less than 50%. There is theoretical concern regarding the rationale for the use of phenobarbital in young children. The main pharmacological effect of phenobarbital is to augment the transmission of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the brain. Paradoxically, GABA has an excitatory effect on the neuronal membrane of the immature brain, which likely persists in humans for the first year of life. The contemporary practice of prescribing phenobarbital as first line for neonatal seizures has been challenged, with a call for randomized placebo-controlled trials in neonates following brain injury, using video electroencephalographic monitoring for the detection of subclinical electrographic neonatal seizures.18 Phenobarbital continues to be an important agent in the treatment of status epilepticus.19 Phenytoin. Introduced in 1938, phenytoin (brand name: Dilantin) is effective for simple partial, complex partial, and generalized tonic-clonic seizures.14 Although it remains a widely used AED throughout the world, its modern use as a chronic oral prophylactic for seizures has been limited by its cosmetic side effects and pharmacokinetics. Phenytoin is 90% protein bound, but this is altered in renal failure and hypoalbuminemia, as well as in neonates and during pregnancy.20 Free serum levels are therefore important to correlate with the standard total levels of 1020 mcgm/mL in these conditions. Phenytoin is metabolized in the liver and, at levels above 20 mcgm/mL, the kinetics become non-linear, so that the half-life becomes prolonged and blood levels may rise rapidly, often with insidious and cumulative adverse clinical effects. In addition, the drug induces hepatic metabolism, which decreases plasma levels of other AEDs, including carbamazepine, felbamate, lamotrigine, tiagabine, and zonisamide. Other drugs are affected as well, including warfarin, cyclosporine, theophylline, oral contraceptives, some analgesics, and some |antibiotics.21 Drugs that are highly protein bound can displace phenytoin and cause higher free phenytoin levels. These are thyroid hormone, tricyclic antidepressants, sulfonamides, and salicylates. Phenytoin is available as a 300 mg extended release capsule that can be administered once daily, since it is absorbed slowly over a 24-hour period.20 This form is a standard adult dose. The half-life in children, however, is shorter and at least twice daily dosing is used, with a typical maintenance dose of 48 mg/kg/day. The medication is available as a
13

50 mg chewable tablet and 125 mg/5 mL suspension. It is difficult to achieve sustained levels in young children, due to poor absorption of oral doses. The suspension tends not to be uniform, and serum levels in patients tend to be unpredictable. The dose-related adverse effects of phenytoin are sedation, ataxia, and nystagmus.22 Uncommon side effects associated with high levels include movement disorders, such as dystonia or chorea, ophthalmoplegia, and aggravation of seizures. Phenytoin may worsen absence, atonic, or myoclonic seizures. Idiosyncratic reactions are a rash seen in 5%10% of patients and a phenytoin hypersensitivity syndrome, characterized by fever, rash, lymphadenopathy, and hepatitis. Cosmetic side effects are gingival hyperplasia, hirsutism, and coarsening of facial features. Long-term use of phenytoin (and phenobarbital) is associated with decreased levels of vitamin D, vitamin K, and folic acid. Phenytoin is an important therapy for status epilepticus, in which case it is preferably administered in the parenteral pro-drug form, fosphenytoin (brand name: Cerebyx). Fosphenytoin is rapidly metabolized to phenytoin via phosphatases. Fosphenytoin has the advantage of being water soluble and, thus, avoiding the sloughing skin reactions and cardiac arrhythmias associated with infusion of parenteral phenytoin within the ethylene glycol vehicle. Carbamazepine. Carbamazepine is an important AED for the treatment of partial seizures and generalized tonic-clonic seizures.14 The traditional brand name form, Tegretol, has been altered, both in its preparation as extended release forms (Tegretol-XR and Carbatrol) and as the oxcarbazepine derivative, discussed later. Carbamazepine has a mechanism of action that is shared by several other AEDs, including phenytoin. These agents block voltage-sensitive sodium channels,23 leading to stabilization of neuronal membranes and inhibition of repetitive firing. Carbamazepine is extensively metabolized by the P450 system and induces its own auto-metabolism. This may lead to otherwise unanticipated lower blood levels and breakthrough seizures after 34 weeks of ongoing treatment, after which this process is complete. The hepatic-inducing properties discussed above with phenobarbital and phenytoin are also associated with carbamazepine. The dosage is typically initiated in children at 510 mg/kg/day, with increases by similar amounts at weekly intervals, to reach a maintenance dose of 1545 mg/kg/day in 23 divided doses. The medica14

tion is available as a 200 mg tablet as well as a 100 mg chewable tablet and 100 mg/5 mL suspension, the latter two being particularly helpful for children. The dose-related adverse effects are drowsiness, diplopia, vertigo, and ataxia. Dermatologic reactions, including Stevens-Johnson syndrome, may occur in the first 6 months of treatment, and there is a crosssensitivity seen in patients who developed a rash using phenobarbital or phenytoin. The serious blood dyscrasias of aplastic anemia and agranulocytosis are rare but occur at least 5 times more in exposed patients than in the general population.24 Hyponatremia is associated with an antidiuretic hormone-like effect and, therefore, serum electrolytes should be checked in a treated patient with an otherwise unexplained change in mental status or seizures. Valproic acid/valproate. Valproic acid (brand name: Depakene) and sodium valproate (brand name: Depakote) were a major advance for pediatric epilepsy patients in particular during their release in 1978, owing to a wide spectrum of action that includes not only generalized tonic-clonic and partial seizures, but also absence, atonic, and myoclonic seizures. This highly effective antiepileptic probably has multiple mechanisms of action, including enhancement of GABA-ergic transmission, blockage of voltage-activated sodium currents, and effects on thalamic calcium currents,25 although the relative contribution of these actions to its clinical effectiveness is unknown. The wide spectrum of action of valproate against different seizure types catapulted it to the AED of choice for epilepsy syndromes that are almost provincial to pediatrics (ie, childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and LennoxGastaut syndrome). It also emerged as a potential therapy, after ACTH, for infantile spasms. The drug is well absorbed after oral administration, and Depakote is an enteric-coated, delayed release formulation, available in capsule and sprinkle forms. Its absorption is not affected by food. The half-life is 15 hours as monotherapy and 89 hours in patients taking hepatic inducers. Its metabolism is hepatic, using multiple pathways, including those used in fatty acid oxidation. The initial pediatric dose is 1015 mg/kg/day, which may be increased at weekly intervals, to maintenance doses in the range of 3060 mg/kg/day in 23 divided doses. There is also a newer intravenous form (brand name: Depacon), which may be used for parenteral loading, when rapid levels are desired. Dose-related adverse effects include sedation, fatigue, ataxia, and tremor. Gastrointestinal toxicity,

manifest by abdominal pain, nausea, diarrhea, or constipation, is minimized by combining with food and using valproate in contrast to valproic acid. Hematologic effects include thrombocytopenia and platelet dysfunction. Mild thrombocytopenia is common, at least partially dose related, and typically transient. The thrombasthenia is usually not clinically significant unless the medication is combined with other medicines that alter coagulation or the patient is undergoing surgery. The most problematic factor associated with valproic acid/valproate is fatal hepatotoxicity apart from otherwise minor elevations in liver transaminases. The fatal complication is usually seen within the first 6 months of therapy, and the high-risk group is children under 2 years of age on multiple AEDs. The risk is approximately 1 in 500 for this group, compared with 1 in 7000 in children of the same age receiving valproate monotherapy, and 1 in 45,000 in patients over 2 years of age on valproate monotherapy.26 Other rare but important idiosyncratic side effects are hyperammonemia, which can be associated with mental status changes, exacerbation of underlying metabolic errors such as mitochondrial disorders, and pancreatitis.27 While all the AEDs studied have been associated with some degree of teratogenesis, valproate in particular has been linked to an increased risk of fetal neural tube defects. While this risk can be lessened with maternal ingestion of supplemental folic acid, this vitamin would need to be started at the very earliest phase of pregnancy. As a result, valproate is avoided, when possible, in women of childbearing age.26 In addition, valproate use is associated with polycystic ovarian syndrome and weight gain. Ethosuximide. Of the traditional AEDs, ethosuximide (brand name: Zarontin) has the distinction of a specific indicationabsence seizures. When ineffective as monotherapy, its efficacy is sometimes enhanced in combination therapy with valproate.28 The mechanism of action of ethosuximide is to modify thalamic T-type calcium currents.29 The genesis of absence seizures is synchronous firing of thalamic relay neurons and the nucleus reticularis of the thalamus, which ultimately leads to generalized spikeand-wave discharges via a cortico-thalamic-cortical loop. This synchronization is dependent on T-type calcium channels, and blockage of this firing disrupts the pathway producing absence seizures. Ethosuximide is initially dosed between 510 mg/kg/day, with maintenance doses usually between 1540 mg/kg/day. The half-life is 30 hours in
15

children, and steady state is reached after 47 days. Enzyme inducers will decrease the half-life, and valproic acid and felbamate may inhibit its metabolism. Common dose-related side effects are sedation, dizziness, headache, and gastric upset. Taking the medicine after meals can improve gastrointestinal adverse effects. Idiosyncratic reactions include rash, leucopenia, agranulocytosis, aplastic anemia, and systemic lupus erythematosus.

The New AEDs


A virtual litany of AEDs entered the U.S. market in the mid-1990s, starting with felbamate in 1993. This was the first major AED to be introduced in 15 years, and there was considerable excitement about high efficacy and safety. The safety was called into question one year following the FDA approval, with reports of aplastic anemia and fatal hepatopathy with 100,000 patient exposures. This tempered the enthusiasm as new AEDs have continued to become available. While all of the new AEDs have been approved with the primary indication being adjuvant therapy for adults with partial seizures, based on the process involved in their testing and approval, their practical use and, in some cases, indications have extended beyond this to the pediatric realm and even nonepilepsy indications. The new AEDs will be presented here based on the chronological order of their FDA approval and availability, with specific comments pertinent to their use in pediatrics. Felbamate. A highly effective AED, felbamate (brand name: Felbatol) was the first agent to demonstrate proven efficacy in Lennox-Gastaut syndrome.30 In light of its potential for serious toxicity to the bone marrow and liver, the medicine was virtually withdrawn from the market one year following its release, although it has continued to play a role in patients with severe epilepsy. It is currently approved for use as adjuvant therapy only for Lennox-Gastaut syndrome, in patients 214 years of age. Felbamate is also approved for use as either adjuvant therapy or for conversion to monotherapy (but not the starting therapy) for patients with severe partial onset and tonic-clonic seizures, where the benefits are felt to outweigh the potential risks. Gabapentin. Gabapentin (brand name: Neurontin) is structurally similar to GABA, but its mechanism of action against seizures is not well understood. There is no protein binding or significant drug-drug interaction. It is eliminated unchanged by the kidney and does not interact with hepatic enzymes.31 Its efficacy and safety have been demonstrated as

monotherapy for patients with newly diagnosed partial seizures,32 and it has compared favorably to carbamazepine33 and lamotrigine34 as monotherapy. Gabapentin is approved for adjunctive therapy for partial seizures in adults as well as children aged 312 years. In clinical practice, it has been regarded as highly effective in pain syndromes, but has not reached enthusiasm for convincing efficacy in epilepsy, as corroborated by a published survey of pediatric epileptologists.35 Lamotrigine. Lamotrigine (brand name: Lamictal) shares a primary mechanism of voltage-sensitive sodium channel inhibition with phenytoin and carbamazepine, yet has a wider spectrum of action than these 2 older agents. Its efficacy has been demonstrated in children having refractory partial onset36 and generalized37 seizures, including Lennox-Gastaut syndrome.38 It compares favorably as monotherapy against carbamazepine39 and phenytoin.40 A placebocontrolled trial of monotherapy in typical absence seizures has demonstrated benefit for lamotrigine.41 An NIH-funded multicenter blinded study comparing valproate, ethosuximide, and lamotrigine for newly diagnosed absence seizures is currently underway. The principal concern with lamotrigine use is the possibility of a potentially life-threatening skin rash. The overall incidence of rash with lamotrigine use is 10%, and Stevens-Johnson syndrome or toxic epidermal necrolysis has an estimated incidence of 1:1000 adults and 1:100200 children.42 Most cases occur within the first several months of therapy. There is an important interaction between valproate and lamotrigine, where the former prolongs the half-life of the latter, and there is an increased incidence of rash when lamotrigine is added as an adjuvant agent to valproate. For this reason, the dosage of lamotrigine must be smaller (initial dose of 0.15 mg/kg/day, with maintenance limited to 15 mg/kg/day) and titrated more slowly when this drug is added to valproate. Children starting on lamotrigine monotherapy may take 0.3 mg/kg/day and increase up to 28 mg/kg/day, whereas children already taking enzymeinducing AEDs may begin at 0.6 mg/kg/day and increase up to 515 mg/kg/day.43 Lamotrigine is approved for children age 2 years and older as adjunctive therapy for partial and primary generalized tonic-clonic seizures, as well as LennoxGastaut syndrome. It has gained a particular role in the treatment of adults with bipolar I disorder. Topiramate. Topiramate (brand name: Topamax) represents an agent with multiple mechanisms of action and thus, logically, may be viewed as having a
16

wide spectrum of action against multiple seizure types. Its effects include inhibition of voltagedependent sodium channels, enhancement of GABAergic activity, anti-glutamatergic effects, and action as a carbonic anhydrase inhibitor. It has linear pharmacokinetics, is excreted unchanged in the urine, with a half-life of approximately 24 hours, and has minor drug-drug interactions. As predicted, efficacy has been demonstrated for the treatment of multiple seizure types, including children with partial seizures,44 generalized tonic-clonic seizures,45 LennoxGastaut syndrome,46 and, to some extent, infantile spasms.47 In general, topiramate has a good safety record, with little evidence for significant organ toxicity. Adverse effects include decreased appetite, weight loss, and nephrolithiasis. Rarely, renal tubular acidosis and closed-angle glaucoma have occurred. Its use has been principally limited by cognitive slowing and behavioral change side effects.48,49 Tiagabine. Tiagabine (brand name: Gabitril) blocks the reuptake of GABA and has demonstrated efficacy as an adjuvant therapy for refractory partial seizures in patients aged 12 years and older. The agent has had a limited role in children, partially due to its association with confusional states. Concomitant EEG studies have demonstrated an increased frequency of nonconvulsive status epilepticus during tiagabine therapy, which resolves on discontinuation of the drug.50 Levetiracetam. Levetiracetam (brand name: Keppra) is a chemical analogue of piracetam, which has been studied for potential nootropism (ie, cognitive enhancement). Levetiracetam is approved as an adjunctive agent for partial-onset seizures in children aged 4 years and older and appears to have both a wide spectrum of action against different seizure types and a good safety record. There are no problems with protein binding or drug-drug interactions. There is no hepatic metabolism and the drug does not induce or inhibit the cytochrome P450 enzyme system. The drug is excreted mostly unchanged in the urine, and dose reduction is recommended if there is renal impairment. Levetiracetam shows similar efficacy to extendedrelease carbamazepine as a first choice monotherapy agent in adults against partial seizures or tonic-clonic seizures.51 Efficacy in pediatrics has been demonstrated for refractory partial seizures in a double-blind placebo-controlled trial of adjunctive therapy.52 Neuropsychiatric adverse effects, including agitation, hostility, anxiety, apathy, depression, and, rarely, psychotic symptoms, have been problematic in pediatric trials.53,54

Oxcarbazepine. Oxcarbazepine (brand name: Trileptal), originally introduced in Europe in 1990 as a derivative of carbamazepine that avoided metabolism to a neurotoxic epoxy metabolite, was approved by the U.S. FDA in 2000. It has a monotherapy indication for partial seizures for children aged 4 years and older, and as adjunctive therapy for patients aged 2 years and older. Oxcarbazepine is rapidly reduced to its 10-monohydroxy derivative, which is the active metabolite. The drug appears to be different than carbamazepine, however. One significant difference is a relative lack of effect on the hepatic cytochrome P450 system. Its effectiveness against seizures appears similar to that of carbamazepine, phenytoin, and valproate. A double-blind study in children and adolescents showed that it is equally efficacious to phenytoin and better tolerated.55 Oxcarbazepine has shown a good safety and tolerability record in children as young as 2 years of age.56 There appears to be less skin reactions, but more frequent hyponatremia, with oxcarbazepine, compared to carbamazepine. Zonisamide. Zonisamide (brand name: Zonegran) is a sulfonamide with effects on both voltage-sensitive sodium channels and T-type calcium channels. It also has some carbonic anhydrase inhibitory effect. It has proven efficacy in patients older than 12 years of age with refractory partial-onset seizures,57 and open label trials suggest efficacy in patients with progressive myoclonus epilepsy.58,59 Adverse reactions include dizziness, somnolence, anorexia, ataxia, and confused thinking. Serious skin reactions have occurred, as well as hyperpyrexia secondary to hypohydrosis. The latter has been noted especially in children during hot weather. Pregabalin. Pregabalin (brand name: Lyrica) is indicated as adjunctive therapy for adults with partial seizures. This drug was originally approved in 2004 for painful diabetic peripheral neuropathy and post-herpetic neuralgia, and, in 2005, for the treatment of epilepsy. Pregabalin is structurally similar to gabapentin. Both drugs appear to bind to the alpha-2-delta subunit of voltage gated calcium channels. Similarly, both drugs appear to have more therapeutic promise for pain syndromes than for epilepsy. There is potential for future study and application of pregabalin in patients having comorbidities where the drug could have multiple beneficial effects.

Successes and Failures: Discontinuation vs Futility of Therapy


Approximately 60% of patients will enjoy freedom from seizures with the first or second prescribed antiepileptic drug.60 A great success in epilepsy management is the successful tapering and subsequent discontinuation of medication in patients who are seizure free for 2 or more years. A large number of studies have shown consistently that 60%75% of children and adults will remain seizure free when AEDs are withdrawn.61,62 The risk of relapse is 25% at 1 year and 29% at 2 years following AED withdrawal. Most recurrences will occur within 6 months, and 60%80% of relapses will occur within 1 year. The presence of an underlying remote encephalopathy, age-of-onset older than 10 years, and the duration of active epilepsy are risk factors for less successful long-term remission following AED withdrawal. According to most studies, the EEG is also predictive, especially in the idiopathic and cryptogenic epilepsies, where the EEG at seizure onset is integral to the epilepsy syndrome diagnosis (eg, absence epilepsy). Other syndrome diagnoses, while closely associated with specific EEG patterns, carry known prognoses. Benign Rolandic epilepsy has a favorable prognosis for remission off chronic AEDs. In contrast, juvenile myoclonic epilepsy has a favorable prognosis for remission on medications, but requires life-long treatment, with virtually certain relapse if AEDs are withdrawn. A longer seizure-freedom period than 2 years is not supported by epidemiologic data as having a higher likelihood of long-term remission after AED withdrawal. The majority of patients who relapse following AED withdrawal are able to resume remission after medication is reinstated, although this may not occur immediately.63 A fundamental problem in epilepsy is that, despite the proliferation of available medications, 30%40% of patients have seizures that are difficult to control. Although 60% of patients will become seizure free with use of the first or second AED, only 3% attain seizure freedom with 2 concomitant AEDs, and none with three.60 If freedom from seizures, as opposed to seizure reduction, is the goal, we have not achieved that with more medication options. Inherited drug resistance proteins affecting the transport of medications through the blood-brain barrier may be among the factors behind multiply drug-resistant seizure disorders.64 A final caveat that may be surprising to clinicians is that some AEDs have the adverse effect of exacerbating seizures, especially at higher dosages. For
17

example, phenytoin toxicity may present with worsening of generalized tonic-clonic seizures. Even at standard doses and levels, multiple AEDs have been associated with worsening of certain seizure types and syndromes, especially the generalized nonconvulsive seizures (Table 2).65
Table 2: Seizures/ Syndrome Absence Myoclonic Juvenile myoclonic epilepsy Lennox-Gastaut syndrome Severe myoclonic epilepsy of infancy Aggravation of Seizures or Epilepsy Syndromes by AEDs CBZ PHT LTG GBP TGB X X X X X X X X X X X X X X X X X

with medically refractory epilepsy is discussed in the next section.


Correspondence to: Phillip L. Pearl, MD Associate Professor of Pediatrics and Neurology Childrens National Medical Center 111 Michigan Ave NW Washington, DC 20010 Tel: (202) 884-2120 Fax: (202) 884-5226 E-mail: ppearl@cnmc.org

References
1. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia. 1993;34:592-596. 2. Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology. 1991;41:965-972. 3. Shinnar S, Berg AT, Moshe SL, et al: The risk of seizure recurrence following a first unprovoked afebrile seizure in childhood: an extended follow-up. Pediatrics. 1996;98:216-225. 4. Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998;338:429-434. 5. Shinnar S, Berg AT, ODell C, et al. Predictors of multiple seizures in a cohort of children prospectively followed from the time of their first unprovoked seizure. Ann Neurol. 2000;48:140-147. 6. Dunn DW, Austin JK, Harezlak J, et al. ADHD and epilepsy in childhood. Dev Med Child Neurol. 2003;45:50-54. 7. Austin JK, Harezlak J, Dunn DW, et al. Behavior problems in children before first recognized seizures. Pediatrics. 2001;107:115-122. 8. Austin JK, Dunn DW, Caffrey HM, et al. Recurrent seizures and behavior problems in children with first recognized seizures: a prospective study. Epilepsia. 2002;43:1564-1573. 9. Goh S, Kwiatkowski DJ, Dorer DJ, Thiele EA. Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology. 2005;65:235-238. 10. Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia. 2005;46(suppl 11):54-61. 11. Patsalos PN, Sander JW. Newer antiepileptic drugs. Toward an improved risk-benefit ratio. Drug Saf. 1994;11:37-67. 12. Wilby J, Kainth A, Hawkins N, et al. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation. Health Technol Assess. 2005;9:1-157. 13. Cramer JA, Mattson RH. Phenobarbital toxicity. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995.
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Landau-Kleffner syndrome/Electrographic X status epilepticus sleep

CBZ = carbamazepine; PHT = phenytoin; LTG = lamotrigine; GBP = gabapentin; TGB = tiagabine

Summary
Epilepsy affects up to 1% of children, and antiepileptic drug therapy represents the major medical intervention for the disorder. The risks of therapy vs seizure recurrences must be weighed by the physician, taking into account the individualized features of that patients epilepsy and life circumstances. The majority of patients, although not all, will experience freedom from seizures with the use of their first or second AED. Available AEDs have proliferated over the past 15 years, with the newer agents typically having broader spectra of action against multiple seizure types and being better tolerated. Yet, there are important and sometimes life-threatening complications associated with the new and older agents. The problem of seizure relapse, whether during or following discontinuation of AED therapy, and multiple drug resistance in a considerable proportion of patients, have led to increasing surgical and alternative therapies for epilepsy. While partial success has been achieved through the availability of more medication options exercising different mechanisms of action, there is much work to be done in the medical treatment of seizures and actual modification of the underlying epilepsy. The use of surgery for children

14. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondary generalized tonic-clonic seizures. N Engl J Med. 1985;313:145-151. 15. Dodson WE, Rust RS. Phenobarbital: Absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 16. Kutt H. Phenobarbital interactions with other drugs. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 17. Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341:485-489. 18. Clancy RR. Neurology Group on Neonatal Seizures. The newborn drug development initiative workshop: summary proceedings from the neurology group on neonatal seizures. Clin Ther. 2006;28:1342-1352. 19. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339:792-798. 20. Treiman DM, Woodbury DM. Phenytoin: Absorption, distribution, and excretion. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 21. Kutt H. Phenytoin. Interactions with other drugs. Part I: Clinical aspects. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 22. Bruni J. Phenytoin toxicity. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 23. Schwarz JR, Grigat G. Phenytoin and carbamazepine: Potential- and frequency-dependent block of Na currents in mammalian myelinated nerve fibers. Epilepsia. 1989:30:286-294. 24. Holmes GL. Carbamazepine toxicity. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 25. White SH. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia. 1999;40(suppl 5):2-10. 26. Dreifus FE: Valproic acid toxicity. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 27. Asconape JJ, Penry JK, Dreifus FE, et al. Valproateassociated pancreatitis. Epilepsia. 1992;34:117-123. 28. Sherwin AL. Ethosuximide clinical use. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs, 4th ed. New York: Raven Press; 1995. 29. Coulter DA, Hugenard JR, Prince DA. Characterization of ethosuximide reduction of low threshold calcium current in thalamic neurons. Ann Neurol. 1989;25:584-593.

30. The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993:328:29-33. 31. Leiderman DB. Gabapentin as add-on therapy for refractory partial epilepsy: results of five placebo controlled trials. Epilepsia. 1994:35(suppl 5):S74- S76. 32. Chadwick DW, Anhut H, Greiner MJ, et al. A doubleblind trial of gabapentin monotherapy for newly diagnosed partial seizures. The International Gabapentin Monotherapy Study Group 945-77. Neurology. 1998;51:1282-1288. 33. Beydoun A. Monotherapy trials with gabapentin for partial epilepsy. Epilepsia. 1999;40(suppl 6):S13-S16. 34. Brodie MJ, Chadwick DW, Anhut H, et al. Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia. 2002;43:993-1000. 35. Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion, 2005. J Child Neurol. 2005;20(suppl 1):S1-S56. 36. Duchowny M, Pellock JM, Draf WD, et al. A placebocontrolled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group. Neurology. 1999;53:1724-1731. 37. Eriksson AS, Nergardh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, doubleblind, crossover study. Epilepsia. 1998;39:495-501. 38. Motte J, Trevathan E, Arvidsson JFV, et al. Lamotrigine for generalized seizures associated with the LennoxGastaut syndrome. Lamictal Lennox-Gastaut Study Group. N Engl J Med. 1997;337:1807-1812. 39. Brodie MJ, Richens A, Yuen AWC. UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet. 1995;345:476-479. 40. Steiner RJ, Dellportas CI, Findley LF, et al. Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin. Epilepsia. 1999;40:601-607. 41. Frank LM, Enlow T, Holmes GL, et al. Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia. 1999;40:973-979. 42. Pellock JM. Lamotrigine. In: Pellock JM, Dodson WE, Bourgeois BFD, eds. Pediatric epilepsy: diagnosis and therapy. 2nd ed. New York: Demos; 2001:461-466. 43. Bergin AM and Connolly M. New antiepileptic drug therapies. Neurol Clin N Am. 2002;20:1163-1182. 44. Ritter F, Glauser TA, Elterman RD, et al. Effectiveness, tolerability and safety of topiramate in children with partial onset seizures. Epilepsia. 2000;41(suppl 1): S82-S85.

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45. Biton V, Montouris GD, Ritter F, et al. A randomized placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology. 1999;53:1130-1137. 46. Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Neurology. 1999;52:1882-1887. 47. Glauser TA, Clarke PO, McGee K. Long-term response to topiramate in patients with West syndrome. Epilepsia. 1998;39:1324-1328. 48. Tatum WO, French JA, Faught E, et al. PADS Investigators. Postmarketing experience with topiramate and cognition. Epilepsia. 2001;42:1134-1140. 49. Bootsma HP, Coolen F, Aldenkamp AP, et al. Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2004;5:380-387. 50. Koepp MJ, Edwards M, Collins J, et al. Status epilepticus and tiagabine therapy revisited. Epilepsia. 2005;46:1625-1632. 51. Brodie MJ, Perucca E, Ryvlin P, et al. Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology. 2007;68:402-408. 52. Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology. 2006;66:1654-1660. 53. Harden C: Safety profile of levetiracetam. Epilepsia. 2001;42(suppl):S36-S39. 54. Kossoff EH, Bergey GK, Freeman, JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia. 2001;42:1161-1163. 55. Guerreiro MM, Vigonius U, Pholmann H, et al. A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res. 1997;27:205-213. 56. Rey E, Bulteau C, Motte J, et al. Oxcarbazepine pharmacokinetics and tolerability in children with inadequately controlled epilepsy. J Clin Pharmacol. 2004;44:1290-1300. 57. Faught E, Ayala R, Mountaris GG, et al. Zonisamide 911 Trial Group. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology. 2001;57:1774-1779. 58. Henry T, Leppik IE, Gumnit RJ, et al. Progressive myoclonus epilepsy treated with zonisamide. Neurology. 1998;38:928-931. 59. Conry JA. Pharmacologic treatment of the catastrophic epilepsies. Epilepsia. 2004;45(suppl 5):S12-S16. 60. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia. 2001;42:1255-1260. 61. American Academy of Neurology, Quality Standards Subcommittee. Practice parameter: A guideline for discontinuing antiepileptic drugs in seizure-free patients: summary statement. Neurology. 1990;47:600-602.

62. Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology. 1994;44:601-608. 63. Chadwick D, Taylor J, Johnson T. Outcomes after seizure recurrence in people with well-controlled epilepsy and the factors that influence it. MRC Antiepileptic Drug Withdrawal Group. Epilepsia. 1996;37:1043-1050. 64. Sisodiya SM, Lin WR, Harding BN, et al. Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain. 2002;125:22-31. 65. Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol. 2005;33:227-234.

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Epilepsy Surgery in the Treatment of Medically Refractory Focal Epilepsy


Deepak K. Lachhwani, MB.BS, MD Staff Pediatric Epileptologist Epilepsy Center Cleveland Clinic Neurological Institute Cleveland, OH

Introduction
Treatment options for epilepsy include older and newer AEDs, epilepsy surgery, neurostimulation, immune modulation, and use of a ketogenic diet. Experience from several surgical series has shown that, after failure of medications, resective epilepsy surgery is the preferred treatment option for carefully selected surgical candidates.1-5 The safety and efficacy of epilepsy surgery over medications has been confirmed in a randomized trial involving adult patients with medically refractory temporal lobe epilepsy.6 In this study, 58% of patients in the surgical group became seizure free, compared to 8% in the medically treated group. The medically treated patients experienced a significantly poorer quality of life, and one patient died during the period of observation. There were no deaths or significant surgical complications in the surgically treated group. However, epilepsy surgery continues to be the most under-utilized treatment modality across all ages, especially in young patients.7 The reasons are multifactorial and stem from controversy surrounding answers to key questions: When does a patient prove to be medically refractory? Who is an ideal surgical candidate? What is the risk of surgery and how does it compare to the risk of ongoing medically refractory seizures? These issues require a specifically tailored clinical judgment in each case and are best addressed by an experienced team. There are certain guiding principles and these are highlighted below.

proving to be medically refractory. Drug resistant epilepsy may be predicted as early as after failure of 2 carefully chosen and adequately tried antiepileptic agents. In a study involving adult and pediatric patients, authors found that seizures were successfully controlled with the first AED in 47% of patients.8 However, only 11% of patients who did not respond to first line therapy had their seizures controlled with any other medication trials. Similar results were found in studies involving only pediatric patients. In this cohort, failure of the first AED has shown to be predictive of poor seizure control. Therefore, failure of 2 AEDs should prompt consideration of alternate options. Lack of consensus regarding seizure control has been another significant impediment in considering surgery. Seizure control may mean control of more intense seizures, or an overall reduction of seizure burden for patients with refractory generalized epilepsy, or for patients who are poor surgical candidates. When faced with such clinical situations, the recourse is a trial of different medications and alternate non-surgical treatment avenues. Focal epilepsy syndromes with a potential to be cured with surgical intervention should be viewed differently and evaluated with the goal of complete seizure control. It may not be appropriate to accept a partial reduction in seizure burden as an acceptable therapeutic endpoint. For surgically remediable focal epilepsy syndromes, this knowledge regarding medical refractoriness and seizure control is especially poignant. Prolonged trials with multiple agents should be avoided whenever possible. A prospective study including more than 600 children with newly-diagnosed epilepsy found that symptomatic epilepsy syndromes, as well as high initial seizure frequency, portend early development of intractable epilepsy.9 Risks of ongoing breakthrough seizures and prolonged exposure to medications should be weighed against the potential for cure with resective surgery, where appropriate.

Medically Refractory Focal Epilepsy


Seizure control with a single, well tolerated antiepileptic medication is the first goal after diagnosis of epilepsy is confirmed. The advent of newer medications has increased the available number of treatment options. The increased number of treatment agents may lead to delay in surgical intervention in otherwise good surgical candidates, until such time that most agents have proved to be ineffective, thereby proving medical refractoriness. It is now clear that a patient does not have to fail all agents before
21

Identification of Epilepsy Surgery Candidates


An ideal surgical candidate is one in whom a discrete brain lesion can explain the observed focal epilepsy syndrome, which can then be safely resected without risk of any neurological morbidity and with reasonable likelihood to render a patient seizure free. While appearing to be a straightforward paradigm, the presurgical evaluation is usually complex and fraught with challenges. Pediatric patients often present with large epileptogenic lesions, frequent daily seizures

where focal clinical features are lacking, and complicated EEG findings, which may be more widespread than the visualized lesion. These findings are in contrast to adult epilepsy patients, where the common epilepsy substrate is a discrete hippocampal sclerosis with concordant clinical seizures and EEG abnormalities, leading to a relatively safe and straightforward surgical strategy. Cornerstones of a presurgical evaluation include careful analysis of seizure semiology (as noted by parents and captured on video EEG), interictal and ictal EEG abnormalities, and investigation for an MRI lesion. Digital video EEG is a powerful tool for documenting clinical seizures with careful attention to detail.10,11 Analysis of recorded data is helpful to appreciate subtle focal motor features that may have been missed. A true seizure burden may be estimated by documenting EEG seizures with little or no accompanying clinical signs,12 and the time-locked video and EEG enable a more accurate diagnosis of focal, multifocal, or generalized epilepsy syndrome. The next step is detection of the epilepsy substrate. Visualization of the underlying epileptogenic lesion is key for the development of a surgical strategy. An MRI is clearly the study of choice for anatomic detail, and techniques have improved vastly. It is important to obtain an MRI study with fine cuts (2 mm thickness), no inter-slice gap, and the correct sequences (T1, T2, and FLAIR) to appreciate the more subtle abnormalities that may be otherwise missed. The period of infancy is characterized by rapid changes, due to physiological maturation of the brain. Unique to this phase of the first few months of life is a changing MRI signal intensity, due to maturation of the gray and white matter. This may eclipse an underlying cortical malformation, and MRI study should be repeated when suspicion of a focal epilepsy syndrome is high. Adjunctive tests, including functional neuroimaging, molecular imaging with specific radioligands, and fiber track imaging (DTI) may further help in implicating a specific brain region as the epileptogenic region. FDG PET is a sensitive test for indicating an area of dysfunction, although it lacks specificity. PET studies with other ligands (ie, AMT, flumazenil, FCWAY) are in various stages of evolution, as are modalities such as DTI and fMRI. These tools are expected to continue to evolve in their role in presurgical evaluation of patients. In select patients, invasive EEG recordings, with the aid of subdural electrodes, may be needed for planning surgical strategy. This is true in non-lesional
22

focal epilepsy cases, where the MRI is normal and clinical data (seizure semiology and EEG) are strongly suspicious for a more discrete epileptogenic zone. Another indication for invasive recording includes functional mapping of the eloquent cortex and its relationship to an epileptogenic region. With precise detail, direct cortical stimulation for delineating functional areas lends itself to a tailored resection, which may spare neurologic function.

Temporal Lobe Epilepsy


Pediatric epilepsy series report a fair variety of epileptogenic substrates removed from the temporal lobe of refractory patients. The most common etiology is focal cortical dysplasia. Low-grade tumor (astrocytoma, ganglioglioma, DNET), vascular malformation, and hippocampal sclerosis may also present with a temporal lobe epilepsy syndrome. This is distinct from adult epilepsy patients, where the most common substrate is hippocampal sclerosis, with the other lesions constituting a small percentage. Patients typically have complex partial seizures, with semi-purposeful automatic movements, partial or complete loss of awareness, and, sometimes, progress to a secondarily generalized tonic-clonic seizure. The EEG shows regional interictal and ictal epileptiform discharges. Routine EEGs may be normal, whereas, in other pediatric patients, interictal and ictal EEG findings may be more diffuse than the visualized MRI abnormality. MRI findings are specific for the underlying etiology, and high resolution techniques, performed by an experienced team, are invaluable. FDG, PET, and PET with other ligands may be performed, as clinically indicated. Seizure outcomes are favorable, and freedom from seizures may be observed in up to 75% of cases.2,13 This rate of seizure freedom is similar to adult patients who are operated on for hippocampal sclerosis. The most frequent complication of temporal lobe surgery is an asymptomatic homonymous superior temporal quadrantanopia.14 The asymptomatic nature of this deficit is reassuring and must be emphasized to families considering surgery. Other complications in adults include impairment in memory function15 and language function (following a resection involving a language dominant temporal lobe).16 Children may have similar vulnerability for memory impairment,17 although large studies to prove this finding are lacking. Compared to adult patients, children are more likely to recover from language impairment, due to their ability to redistribute function, by virtue of plasticity.

Illustrative Case 1. Right-handed girl, aged 6 years, was referred for staring episodes. The episodes began 7 months prior to the visit. During the initial presentation, she was noted by parents to be distracted for 3060 seconds. However, she seemed to have preserved responsiveness. Afterward she developed a headache, felt tired, and wanted to sleep. The episodes were sporadic, occurring once every few weeks, and were felt to be migraine headaches. During the following months, the patient started describing these episodes as mind dreams, with features suggestive of rare visual hallucinations. She also had clear loss of awareness during some episodes and was amnestic to the event afterwards. Her MRI brain and routine EEG were normal, and she was presumptively started on oxcarbazepine, to treat possible seizures. Symptoms continued with increasing frequency (12/week). Her antenatal history and past medical history were normal. She had age-appropriate cognitive skills, and no past history of meningitis, febrile seizures, or head injury. The family history was remarkable for epilepsy in 3 maternal aunts and mother suffered of migraine headaches. Physical examination and neurological examination were within normal limits. She was admitted for video EEG monitoring and further testing. Her interictal EEG showed continuous slowing and intermittent sharp waves in the left temporal region (Figure 1a). One complex partial seizure was recorded, during which she manifested staring, repetitive eye blinking, semipurposeful hand movements, and some fidgeting movements. Ictal EEG showed a left temporal seizure (Figure 1a).
Figure 1a: Patient Case: Female, Aged 6 Years

for either a cortical malformation or a low-grade neoplasm. This lesion was best visualized in the FLAIR sequence (Figure 1b). FDG PET showed a concordant hypometabolism (Figure 1c).
Figure 1b: Patient Case: Female, Aged 6 Years

Figure 1c: Patient Case: Female, Aged 6 Years

She was presented at the epilepsy surgery conference. It was appreciated that she had a lesion causing left temporal epilepsy and had failed one antiepileptic medication. Options included serial follow-up, with continued medication trials for optimizing seizure control, or consideration of epilepsy surgery. Although she had failed only one antiepileptic medicine, the possibility of an underlying neoplasm raised concerns for future growth potential of this lesion, with attendant complications. Furthermore, the lesion was felt to be safely resectable, and, therefore, surgery was recommended over further medication trials. She underwent a resection of the lesion, with sparing of mesial temporal structures, at 6 years of age. Histopathology showed a low-grade glioma. At 10 years of age, she remains seizure free, has normal neurological function, and is on no AEDs.

An MRI was obtained using T1, T2, and FLAIR sequence, with thin contiguous slices, showing an anterior left temporal non-enhancing lesion suspicious
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Extratemporal and Multilobar or Hemispheric Epilepsy


Extratemporal and multilobar or hemispheric epilepsy substrates are more frequently reported in surgical series involving children. Examples of lesions include large antenatal or perinatal cerebral infarction, multilobar or hemispheric cortical malformation (hemimegalencephaly), Sturge-Weber syndrome, and Rasmussen chronic focal encephalitis. Presentation may involve catastrophic seizure burden early in the course of illness, pre-existing focal neurological deficits (hemiparesis, hemianopia), and neurocognitive impairment at time of epilepsy onset or at the time of surgical consideration. Presurgical evaluation may be complicated by diffuse or generalized EEG findings. However this does not necessarily exclude a focal or unihemispheric epilepsy syndrome.18 Careful attention to the neurologic exam, for pre-existing deficits, seizure semiology, or MRI findings, and other adjunctive tests may point to an underlying focal epilepsy syndrome, despite diffuse EEG findings. Surgery at an experienced pediatric epilepsy center may be offered, if the risks of catastrophic epilepsy outweigh the surgical risks. The optimum surgical procedure may involve large multilobar resection or a hemispheric ablation (functional or anatomic hemispherectomy). When severe epilepsy presents with a pre-existing motor and visual field deficit (as is often seen in hemispherectomy candidates), surgery may be offered without risk of new neurological morbidity. In some patients with no pre-existing fixed deficit, post-operative homonymous hemianopia, hemiparesis, and language deficits may be mitigating factors, when the proposed epileptogenic area for surgical removal is in proximity with these eloquent cortical areas. Extraoperative studies with subdural electrodes may be judiciously used, especially in older children, for functional mapping of the eloquent cortex, which can then be avoided. The strategy in Rasmussen encephalitis is based on aggressive non-surgical management until onset of motor deficit, when definitive intervention with hemispherectomy may be offered at no further risk of motor deterioration. The visual deficit cannot be avoided and needs to be discussed before proceeding with surgery. A seizure-free outcome is observed less frequently with these types of patients compared to temporal lobe epilepsy surgery patients. Approximately 54% of patients with extratemporal or hemispheric resection became seizure free in one series.2 Within
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this group, significantly better results have been noted when results were analyzed by etiology. Patients with low-grade tumors were more likely to become seizure free (82%), compared to patients with cortical malformation (52%). In a series of only hemispherectomy patients, authors noted 65% seizure-free outcomes.19 These reports and other studies highlight that seizure freedom may depend on underlying etiology, with some substrates more amenable to surgical cure than others. However the overall improvement from intractable seizures is vastly better than with continued medications. Illustrative Case 2. A male infant, aged 8 weeks, was transferred to our epilepsy center due to medically refractory status epilepticus. Seizures had started on day 3 of life and were increasing in frequency and intensity, despite use of multiple antiepileptic medications. The seizures occurred daily in clusters, with 1030 seizures per cluster, and 5 seizure clusters every day. The mother described the individual seizures as flexor spasms, with facial grimacing and tonic stiffening of all 4 extremities, followed by rapid eye blinking lasting up to 30 seconds. During some seizures, the eye blinking was more noticeable on the right side. After the cluster of seizures, the infant remained tired and exhausted for 23 hours. Medications were ineffective and, during one stronger seizure, the infant suffered a cardiac arrest while being transported to the hospital. He was successfully resuscitated. He had remained in the hospital for the majority of his first 8 weeks of life, for management of refractory epilepsy. Attempts to discharge him home had failed, as he would be brought to the emergency room within 24 hours of discharge with an intense seizure cluster or an acute life threatening emergency due to cyanosis, respiratory depression, and bradycardia. He was on therapeutic doses of 4 antiepileptic medications: lamotrigine, leviteracetam, oxcarbazepine, and phenobarbital. He had previously failed a trial of phenytoin and intravenous pyridoxine. The mother had received adequate care during pregnancy, with close follow-up due to polyhydramnios. The infant was born at 36 weeks gestation, with a birth weight of 6 lbs, 3 oz. His postnatal course was unremarkable, and he was discharged home on day 2 with no concerns. His development was showing signs of stagnation. At 8 weeks of age, he made eye contact and registered his mothers presence, but he rarely smiled and had little head control. The mother felt this was largely due to heavy doses of medications and

frequent seizures. She noted that on days with fewer or less intense seizures, he looked brighter and attempted to hold his head better. There was no history of head trauma or CNS infection. His mother had a history of cerebral vascular malformation and had experienced 2 generalized motor seizures. She remained seizure free on oxcarbazepine. Two maternal first cousins had histories of seizuresone with febrile seizures and the other with epilepsy of unknown etiology. On exam, length and head circumference were appropriate for age and the infants weight was 4.7 kilograms. He had airway-conducted sounds suggestive of moderate to severe resistance in the upper airways. The neurological exam was suggested preferential use of the left upper extremity, with decreased spontaneous movements, and mild hypotonia of the right upper extremity. There was intermittent fisting, with flexion of the thumb across the palm in the right hand. Strength and reflex testing did not demonstrate any obvious asymmetry. The infant was admitted to the epilepsy monitoring unit. An interictal EEG showed modified hypsarrhythmia, lateralized to the left hemisphere (Figure 2a). This was characterized by high amplitude bursts of sharp waves, which occupied 40%50% of the record. Multiple epileptic spasms, characterized by clusters of sudden forward head flexion associated with bilateral arm and leg flexion, lasting 15 seconds at a time, were seen. The EEG seizure pattern was generalized and showed diffuse electrodecrement, followed by superimposed low-amplitude paroxysmal fast activity, corresponding to the individual spasms (Figure 2b). Intermixed with the spasms described above, the infant had distinct seizure episodes, characterized by arrest of activity, bilateral eye blinking, and right face pulling, followed by right arm extension prior to a more generalized clonic motor seizure. The ictal EEG pattern was lateralized to the left hemisphere during these seizures (Figure 2c). An MRI of the brain showed an extensive malformation of cortical development involving the left cerebral hemisphere (Figure 2d).

Figure 2a: Patient Case: Male Infant, Aged 8 Weeks

Figure 2b: Patient Case: Male Infant, Aged 8 Weeks

Figure 2c: Patient Case: Male Infant, Aged 8 Weeks

Figure 2d: Patient Case: Male Infant, Aged 8 Weeks

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At the epilepsy surgical conference, the team noted left hemispheric epilepsy due to an underlying cerebral malformation, manifesting as medically refractory clinical and EEG status epilepticus. He had a subtle left hand preference, with no demonstrable weakness in strength. The group agreed unanimously that continued medication trials were likely to be futile and would expose him to a significant risk of morbidity and mortality due to refractory status epilepticus. His risks were further compounded due to his very young age. Therefore, surgical removal of the brain malformation (anatomic left hemispherectomy) was felt to be the preferred treatment option. It was also realized that epilepsy surgery would result in worsening of the pre-existing subtle hemiparesis, as well as creating a new fixed homonymous visual field deficit. Overall, the risk of continued refractory status epilepticus was deemed to be life threatening and to supersede the morbidity issues surrounding surgery. The bioethics team was urged to meet with the family, to highlight the complicating features of the case before pursuing any treatment options. The family elected surgery. A hemispherectomy was performed at 9 weeks of age (Figure 2e). Histopathology showed a severe cortical dysplasia, with microcalcifications and gliosis. Status epilepticus was stopped immediately following surgery. At 2 years age, the boy remains seizure free, with reduction of his seizure medications. His family shares that he has a very bright and cheerful disposition and that he continues to make developmental progress. He has a right hemiparesis and right homonymous hemianopia, as was expected.
Figure 2e: Patient Case: Male Infant, Aged 8 Weeks

stiffening of his whole body, which was worse on the right side (bilateral asymmetric tonic seizures), lasting 12 minutes, and occurring 14 times per day. The second seizure type was brief and manifested with 3040 second episodes of right face and arm twitching, 14 times per day. His seizures did not respond to several medications, including phenobarbital, phenytoin, oxcarbazepine, topiramate, and leviteratcetam. He had also failed 2 trials of IVIG therapy and a trial of IV steroids. Over the preceding 12 months, seizures had increased in severity and frequency. At the time of presentation to our institute, he had continuous myoclonic jerking of his right face and extremities during wakefulness and sleep (epilepsia partialis continua). In addition, he had weakness of the right side and the family noticed he was less sociable and withdrawn. He did not speak much and seemed to have lost his language and cognitive faculties. His language was reduced to monosyllables and single words (mama, dada, thirsty, etc). Previous evaluations had confirmed left hemispheric epilepsy. Multiple brain MRIs were normal, and other studies had not revealed an underlying diagnosis of epilepsy. The boy had undergone a brain biopsy, which showed mild non-specific lymphocytic infiltrate, and was negative for CMV and HSV. The boy was born prematurely. The mother was diagnosed with placenta accreta. Birth was at 30 weeks gestational age, due to premature rupture of the membranes. His apgar scores were 9 at 1 minute, and 9 at 5 minutes. He had an uneventful postnatal course, apart from hyperbilirubinemia (treated with phototherapy) and apnea of prematurity. He had normal developmental milestones and was age appropriate until onset of the seizures. There was no history of febrile seizures, CNS infection, or head trauma. A family history was unremarkable for epilepsy, neurodegenerative, or neurometabolic disease. Physical examination showed a quiet and withdrawn child, with poor eye contact, no interest in his surroundings, and minimal interaction with his family or other care providers. He had a right hemiparesis and concurrent right epilepsia partialis continua. There were no other abnormal findings on physical or neurological exam. Investigations showed continuous slowing and sharp waves from the left hemisphere (Figure 3a) and there was no clear EEG correlation of the right body myoclonic jerks (Figure 3b). Five clinical seizures were recorded, showing a bilateral asymmetric tonic seizure (right>left body), evolving into a right face and arm clonic seizure. The corresponding ictal EEG
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Illustrative Case 3. A boy, aged 4 years, presented with intractable seizures. Onset of the seizures was at 2 years of age, before which he was believed to be normal. Seizure description suggested 2 kinds of events. The first type involved a tonic

was non-localizable, due to the presence of a generalized electrodecrement at the onset (Figure 3c), followed by mixed rhythms involving the left and right cerebral hemisphere (Figure 3d).
Figure 3a: Patient Case: Male, Aged 4 Years

Figure 3d: Patient Case: Male, Aged 4 Years

Figure 3b: Patient Case: Male, Aged 4 Years

Additionally, review of the MRI was suggestive of a subtle volume loss involving the left hemisphere, with mild enlargement of the left lateral ventricles and prominence of sulci in the overlying cortex (Figure 3e). An FDG PET study showed a diffuse left cerebral hypometabolism (Figure 3f).
Figure 3e: Patient Case: Male, Aged 4 Years

Figure 3c: Patient Case: Male, Aged 4 Years Figure 3f: Patient Case: Male, Aged 4 Years

The boys case was presented at the surgical epilepsy conference. The clinical presentation of focal epilepsy, progressive neurological impairment (cognitive and language deficit and right hemiparesis), and
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evidence of volume loss shown by the MRI were most consistent with chronic progressive focal encephalitis (Rasmussen encephalitis). Further medicines were not likely to halt disease progression. A left functional hemispherectomy (including resection of insula) was offered to cure the epilepsy, avert accompanying epileptic encephalopathy, and allow early plasticity to facilitate recovery. The family agreed to proceed, with knowledge that a language and motor deficit were already present. In addition, a right visual field deficit would be expected after surgery. Surgery on the 4-year-old boy was performed 4 weeks after presentation to our institution (Figure 3g). Histopathology showed evidence of neuronal loss, microglial nodules, and peri vascular lymphocytic infiltrate (features consistent with chronic progressive encephalitis).
Figure 3g: Patient Case: Male, Aged 4 Years

while none of the surgically treated patients died.6 In a prospectively followed cohort who had epilepsy surgery, authors found a reduced risk of epilepsyassociated death and reported that excess mortality associated with refractory epilepsy is eliminated after epilepsy surgery when seizures are abolished.22 Ongoing seizures need long-term use of medications that can be associated with risk of adverse effects. These adverse effects were frequently observed with the older AEDs, and, although seen less often, the newer AEDs are not without the risk of some significant adverse effects.23,24 Beyond the immediate risks associated with uncontrolled seizures and chronic use of medications, the pediatric epilepsy population poses additional concerns. Neurocognitive development and neuroplasticity are characteristic virtues of the early years of life. It is well recognized that chronic, uncontrolled seizures have a deleterious and irreversible effect on neurodevelopment.25 The presence of continued seizures vs early control of seizures is a significant factor affecting cognitive outcomes in patients with tuberous sclerosis26 and other epilepsy syndromes.27 In many patients, cognitive impairment is multifactorial, so that the primary underlying brain condition itself may have a deleterious effect on learning. However, uncontrolled seizures seem to add insult to injury. Every attempt must be made to control seizures expeditiously and prevent an irreversible epileptic encephalopathy. An immature and developing brain also has tremendous potential for recovery from a more discrete insult, due to its inherent plasticity. Transfer of language is more readily observed when a languagedominant hemisphere is injured in a young brain than when an adult brain is faced with the same insult.28,29 Elegant animal model studies have confirmed human observations of this potential for recovery in a young brain in other functional areas as well. Surgical intervention early in the course of epilepsy is likely to provide the best chance for the preserved areas of the brain to redistribute function after the epileptogenic cortex is removed.30

The boy is now 8 years of age, seizure free, and free of antiepileptic medications. On exam, he is very sociable, has a fixed right hemiparesis, and a right homonymous visual defect. The parents note that he continues to make progress in language and other areas of neurodevelopment, and that his visual deficit does not impair his daily activities.

Risks of Ongoing Seizures


Most apparent risks of ongoing seizures are inherent to the morbidity and mortality risks associated with the seizures themselves. Frequent seizures prevent normal functioning, and even mild seizures adversely affect the quality of life of the patient and caregivers.20 Every mild seizure has the potential to become secondarily generalized, requiring sophisticated and timely medical intervention. Risk to life has been well documented.21 There was one death in the medically treated arm of the study mentioned earlier comparing epilepsy surgery and medical treatment,
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Timing of Surgery
These unique features of a young brains potential for neurocognition and neuroplasticity provide strong impetus for early intervention with surgical cure in selected candidates. Surgical series have documented improved post-operative development in patients with better preoperative cognition and early cessation of

seizures.1,31,32 Authors reporting on infants who underwent resective epilepsy surgery noted marked catchup developmental progress in several patients who were operated on early in childhood, with good seizure outcomes.1 Another surgical series involving young patients undergoing hemispherectomy noted improved psychomotor development in all patients.31 Subsequently, this group also noted that a high preoperative cognitive function and cessation of seizures were associated with better post-operative intellectual outcomes.32 Timing of surgery is influenced by the presence of neurological deficit. In patients with pre-existing motor or visual field deficit, such as in patients with hemispheric malformation or large antenatal or perinatal stroke, no further neurological deficits may be anticipated after surgery, and intervention may be planned early after failing on 2 medications. Patients with chronic focal progressive epilepsy syndrome, such as Rasmussen encephalitis, are more likely to be tried on multiple antiepileptic medications and immune modulation before surgical intervention (hemispherectomy) is offered.33,34 A hemispherectomy is curative for this refractory catastrophic focal epilepsy. However, it also results in a fixed hemiparesis and hemianopia. It may be more ethically acceptable to wait for the natural course of this progressive catastrophic neurological syndrome to manifest, with hemiparesis, before proceeding to surgical intervention. However, the severity of the illness may not allow this luxury of time in some cases, and a seamless communication between medical experts, ethics team, and family members is essential for appropriate and timely intervention.

Correspondence to: Deepak K. Lachhwani, MB.BS, MD Staff Pediatric Epileptologist S-51. Epilepsy Center Cleveland Clinic Neurological Institute Cleveland, OH 44195 Tel: (216) 445-9818 Fax: (216) 445-6813 E-mail: lachhwd@ccf.org

References
1. Wyllie E, Comair YG, Kotagal P, Raja S, Ruggieri P. Epilepsy surgery in infants. Epilepsia. 1996;37:625-637. 2. Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol. 1998;44:740-748. 3. Duchowny M, Jayakar P, Resnick T, et al. Epilepsy surgery in the first three years of life. Epilepsia. 1998;39:737-743. 4. Delalande O, Fohlen M, Bulteau C., Jalin C. Surgery for intractable focal epilepsy in children. Rev Neurol (Paris). 2004;160:S195-S202. 5. Terra-Bustamante VC, Inuzuka LM, Fernandes RMF, et al. Outcome of hemispheric surgeries for refractory epilepsy in pediatric patients. Childs Nervous System. 2007;23:321-326. 6. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311-318. 7. Wieser HG, Silfvenius H. Overview: epilepsy surgery in developing countries. Epilepsia. 2000;41(suppl 4):S3-S9. 8. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314-319. 9. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology. 2001;56:1445-1452. 10. Nordli DR. Usefulness of video-EEG monitoring. Epilepsia. 2006;47:26-30. 11. Benbadis SR, O'Neill E, Tatum WO, Heriaud L. Outcome of prolonged video-EEG monitoring at a typical referral epilepsy center. Epilepsia. 2004;45:1150-1153. 12. Kallen K, Wyllie E, Luders HO, Lachhwani D, Kotagal P. Hypomotor seizures in infants and children. Epilepsia. 2002;43:882-888. 13. Duchowny M, Levin B, Jayakar P, et al. Temporal lobectomy in early childhood. Epilepsia. 1992;33:298-303. 14. Hervas-Navidad R, Altuzarra-Corral A, Lucena-Martin JA, Castaneda-Guerrero M, Vela-Yebra R, Sanchez A. [Defects in the visual field in resective surgery for temporal lobe epilepsy] Article in Spanish. Rev Neurol. 2002;34:1025-1030. 15. Gleissner U, Helmstaedter C, Schramm J, Elger CE. Memory outcome after selective amygdalohippocampectomy: a study in 140 patients with temporal lobe epilepsy. Epilepsia. 2002;43:87-95.

Summary
For good surgical candidates with medically refractory focal epilepsy, an early and successful surgical intervention is likely to avert prolonged suffering. The paradigms for defining medical refractoriness and acceptable seizure control should be tailored specifically to clinical situations with potential for complete cure from seizures. This is especially true when facing a relatively narrow window of opportunity during the crucial first few months of a patients life. It is, therefore, extremely important to make an accurate epilepsy syndrome diagnosis and to exercise vigilance in identifying medically refractory focal epilepsy patients, so that several futile trials of ineffective medications, over many years, may be avoided.

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16. Saykin AJ, Stafiniak P, Robinson LJ, et al. Language before and after temporal lobectomy: specificity of acute changes and relation to early risk factors. Epilepsia. 1995;36:1071-1077. 17. Szabo CA, Wyllie E, Stanford LD, et al. Neuropsychological effect of temporal lobe resection in preadolescent children with epilepsy. Epilepsia. 1998;39:814-819. 18. Gupta A, Wyllie E, Lachhwani DK, Kotagal P, Bingaman W. Children with generalized scalp EEG discharges and focal brain lesions could they be surgical candidates? Letter. 2004. 19. Kossoff EH, Vining EP, Pillas DJ, et al. Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology. 2003;61:887-890. 20. Mihara T, Inoue Y, Matsuda K, et al. Recommendation of early surgery from the viewpoint of daily quality of life. Epilepsia. 1996;37(suppl 3):33-36. 21. Ryvlin P, Montavont A, Kahane P. Sudden unexpected death in epilepsy: from mechanisms to prevention. Curr Opin Neurol. 2006;19:194-199. 22. Sperling MR, Harris A, Nei M, Liporace JD, OConnor MJ. Mortality after epilepsy surgery. Epilepsia. 2005;46(suppl):49-53. 23. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004; 62:1261-1273. 24. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004; 62:1252-1260. 25. Shields WD. Catastrophic epilepsy in childhood. Epilepsia. 2000; 41(suppl 2):S2-S6. 26. Shepherd CW, Houser OW, Gomez MR. MR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. AJNR Am J Neuroradiol. 1995;16:149-155. 27. Asarnow RF, LoPresti C, Guthrie D, Elliott T, Cynn V, Shields WD. Developmental outcomes in children receiving resection surgery for medically intractable infantile spasms. Dev Med Child Neurol. 1997;39:430-440. 28. Boatman D, Freeman J, Vining E, et al. Language recovery after left hemispherectomy in children with late-onset seizures. Ann Neurol. 1999;46:579-586. 29. de Bode S, Curtiss S. Language after hemispherectomy. Brain Cogn. 2000; 43:135-138. 30. Voets NL, Adcock JE, Flitney DE, et al. Distinct right frontal lobe activation in language processing following left hemisphere injury. Brain. 2006;129:754-766.

31. Maehara T, Shimizu H, Shigetomo R, Tamagawa K. [Functional hemispherectomy for children aged 2 years or less for the treatment of intractable epilepsy caused by cortical dysgenesis]. Article in Japanese. No To Hattatsu. 2000;32:395-400. 32. Maehara T, Shimizu H, Kawai K, et al. Postoperative development of children after hemispherotomy. Brain Dev. 2002;24:155-160. 33. Bien CG, Widman G, Urbach H, et al. The natural history of Rasmussen's encephalitis. Brain. 2002;125:1751-1759. 34. Granata T, Fusco L, Gobbi G, et al. Experience with immunomodulatory treatments in Rasmussens encephalitis. Neurology. 2003; 61:1807-1810.

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